Foamable formulation

ABSTRACT

The present invention provides DMSO-containing foamable formulations, methods for preparation, and methods of treatment. The formulations can provide good permeability and bioavailability at the target site. Preferably, the formulations are useful for treating osteoarthritis. In one embodiment, the invention provides a foamable formulation for topical use, said formulation comprising DMSO, polyalkylene glycol alkyl ether, an active agent, a monohydric lower alcohol, a diol, and water. Preferably, the active agent is a non-steroidal anti-inflammatory drug, such as diclofenac sodium or ibuprofen.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Patent ApplicationPCT/US11/28004 (filed Mar. 10, 2011), which claims the benefit of U.S.Provisional Application No. 61/312,629 (filed Mar. 10, 2010). Thecontents of these priority documents and all other references disclosedherein are incorporated in their entirety for all purposes.

BACKGROUND OF THE INVENTION

A foam is a multiphase mixture comprising bubbles of a gas phase thatare separated by a liquid or solid layer (a film). Pilpel N., Foams inpharmacy, Endeavour 9: 87-91 (1985); Durian, D. J. and Weitz, D. A.,“Foams” in Kirk-Othmer Encyclo. Chem. Tech., 4th ed., 11: 783-805(1994). Liquid-based foams are dynamic systems that eventually collapseor break to release the gas phase. A foam's collapsibility orbreakability depends on numerous physical properties of its components,such as the liquid phase's viscosity and surface tension, the gasphase's pressure and bubble size, and the film's elasticity.

To persist for more than a short period, a foam preferably includes atleast one foaming agent such as a protein or surfactant. Surfactantsstabilize the foam, e.g., by inhibiting bubble coalescence. Zhao, Y.;Brown, M. B.; Jones, S. J., Pharmaceutical foams: are they the answer tothe dilemma of topical nanoparticles?, Nanomedicine, in press (2010).

As discussed in WO2009/090558, the types of topical foam vehiclesinclude aqueous foams, such as commonly available shaving foams;hydroalcoholic foams; emulsion-based foams, comprising oil and watercomponents; and oleaginous foams, which comprise high levels of oil.Lower alcohol compounds may increase penetration, but may also dry theskin and may cause stinging if applied to wounds or sores. Oilycomponents may be emollients, moistening the skin, but may also leave anunpleasant greasy residue.

Some foams are long-lasting (e.g., shaving creams or gels). Other foamsare quick-breaking and collapse soon after application, which can allowmore rapid absorption of the foam's active agent. However, if the foambreaks too quickly, it will be difficult to apply. Quick-breaking foamsmay be destabilized by body heat (thermolabile) or by force (labile tomechanical stress), which allows easy spreading over the site ofapplication.

Mere combination of basic ingredients does not automatically producefoams suitable for pharmaceutical or cosmetic use. Small changes in thefoam base, such as the addition of active ingredients or co-solvents,may destabilize a foam. Similarly, selection within a group ofingredients may provide a foam or class of foams that providesunpredictably superior properties.

For example, DMSO is a polar aprotic solvent with lower surface tensionthan water. DMSO has penetration-enhancing properties that make it anattractive as a solvent, but it is difficult to foam. A DMSO-based foamwould likely provide improved penetration of its active ingredient inaddition to the other advantages of a foam.

Although a foam's properties can be difficult to predict, propertiessuch as collapsibility or stiffness are crucial for the foam's intendeduse. For example, a pharmaceutical foam for internal application mustsometimes persist for hours or days to release an active agent slowly. Apharmaceutical foam for topical application to skin must break down morequickly, but not so quickly that the liquid or solid phase will drip offthe skin before absorption of sufficient active agent.

Qualities such as foam stability, easiness to spread, and appropriatebreakability upon application to the skin or joint are desirablefeatures. These characteristics can be measured by conducting foamformation and foam collapsibility experiments. Foam formation (foamheight vs. time), for example, is predictive of the generation of asprayable/spreadable foam. The rate of collapsibility is an importantproperty in the appropriate administration of the foam.

Many foams are generated by dispensing a foam base in combination with adissolved, gaseous propellant that expands upon release from a containerto produce the foam's bubbles (e.g., those disclosed in WO 2010/125470).However, propellant-based foams take longer to collapse as compared toquick-breaking aqueous foams and as such may not be useful in certainapplications. Manufacturing a propellant-based composition can also bemore costly and difficult, and the associated canisters can harm theenvironment. Additionally, there is an increased risk in handling andtransporting pressurized canisters due to the dangers associated withtheir explosive properties. It is therefore preferable to develop acomposition comprising DMSO that is foamable in the absence of apropellant.

Pharmaceutical foams have been used in wound and burn dressings,contraception, and topical drug delivery. They are easy to applyuniformly to skin, less messy than cream or liquid dosage forms, andless irritating to sensitive or abraded skin. Zhao, Y. et al., Id. Thesuperior properties of foams may enhance patient compliance. Thedispensing means of a foam formulation can help to prevent contaminationof the container during application. For at least these reasons, foamsare attractive dosage forms for topically absorbable active agents.

Osteoarthritis (OA) is a chronic joint disease characterized byprogressive degeneration of articular cartilage. Symptoms include jointpain and impaired movement. OA is one of the leading causes ofdisability worldwide and a major financial burden to health caresystems. It is estimated to affect over 15 million adults in the UnitedStates alone. See Boh L. E. Osteoarthritis. In: DiPiro J. T., Talbert R.L., Yee G. C., et al., editors. Pharmacotherapy: a pathophysiologicalapproach. 4th ed. Norwalk (CT): Appleton & Lange, pp. 1441-59 (1999).

Oral non-steroidal anti-inflammatory drugs (NSAIDs) are a mainstay inthe management of OA. Oral NSAIDs are also commonly used in themanagement of pain associated with injuries such as minor strains,sprains and contusions. These drugs are thought to exert their analgesiceffect by impeding the production of signaling molecules calledprostaglandins through inhibition of the cyclooxygenase (“COX”) enzyme.The COX enzyme has two isoforms, COX-1 and COX-2. Traditional NSAIDsinhibit both isoforms of the COX enzyme, while the selective COX-2(coxib) class of NSAIDs preferentially inhibits COX-2.

NSAIDs have analgesic, anti-inflammatory, and antipyretic effects andare useful in reducing pain and inflammation. They are, however,associated with serious potential side effects including nausea,vomiting, peptic ulcer disease, and gastrointestinal (GI) hemorrhage.Although selective COX-2 inhibitors produce fewer gastrointestinal sideeffects, they may increase the risk of thrombotic events (e.g., strokeor heart attack). Because of this potential side effect, most of theselective COX-2 inhibitors have been withdrawn from the market.

Topical NSAIDs offer the possibility of achieving local therapeuticbenefit while reducing or eliminating the risk of systemic side effects.Difficulties in topical NSAID treatment of OA or minor injuriespartially arise from the difficulty associated with delivering atherapeutically effective dose of the NSAID through the skin in a mannerthat makes the treatment itself tolerable. It is generally believed thatclinical efficacy in OA requires absorption of the active ingredient andits penetration in sufficient quantities into underlying inflamedtissues including the synovium and synovial fluid of joints. SeeRosenstein, Topical agents in the treatment of rheumatic disorders,Rheum. Dis. Clin North Am., 25: 899-918 (1999).

Various factors can affect the absorption rates and penetration depth oftopical pharmaceutical preparations, including the nature of the activeingredient, the nature of the vehicle, the pH, and the relativesolubility of the active in the vehicle versus the skin (Ostrenga J. etal., Significance of vehicle composition I: relationship between topicalvehicle composition, skin penetrability, and clinical efficacy, Journalof Pharmaceutical Sciences, 60: 1175-1179 (1971)). More specifically,drug attributes such as solubility, size and charge, as well as vehicleattributes such as the drug dissolution rate, spreadability, adhesion,and ability to alter the membrane permeability can each have significanteffects on permeability. The skin barrier also can be compromised byphysical methods, such as iontophoresis, ultrasound, electroporation,heat, and microneedles.

Topical NSAIDs take various forms such as liquids, gels, ointments andsalves. Pharmaceutical foams are formed from the dispersion of a gasphase in a second immiscible liquid or solid phase. Pharmaceutical foamshave been used in wound and burn dressings, contraception and topicalskin delivery. The collapsibility or breakability of a pharmaceuticalfoam is often unpredictable and follows no particular theory. However,the feature of collapsibility or stiffness of a foam is crucial for manyuses.

In light of the foregoing, there is a need for a topical DMSO foamformulation such as a topical NSAID foam suitable for long-term use inthe treatment of OA. A diclofenac or ibuprofen foam would be especiallyuseful. The challenge has been to develop a formulation that willdeliver the active agent to the underlying tissue in sufficientconcentration to treat a disorder, possibly on a long-term basis, whilestill providing a foam with an appropriate collapsibility orbreakability. The present invention satisfies these and other needs.

BRIEF SUMMARY OF THE INVENTION

The present invention relates generally to foamable formulations andmethods of using the foamable formulations to treat pain. In a preferredembodiment, the foamable formulation comprises dimethyl sulfoxide (DMSO)and an active agent. More preferably, the active agent is anon-steroidal anti-inflammatory drug (NSAID) such as diclofenac sodiumor ibuprofen. In another preferred embodiment, the method of treatmentis directed to pain associated with OA or minor injuries.

In one embodiment, the invention provides a foamable formulation, theformulation comprising, consisting essentially of, or consisting of: (i)DMSO; (ii) an active agent; (iii) a monohydric lower alcohol; (iv) adiol; (v) a polyalkylene glycol alkyl ether; and (vi) water. Optionally,the formulation comprises glycerol.

Alternatively, the invention provides a foamable formulation, theformulation comprising: (i) DMSO; (ii) an active agent; and (iii) apolyalkylene glycol alkyl ether. Preferably, the formulationadditionally comprises (iv) a diol; and (v) water. Optionally, theformulation comprises glycerol. Preferably, the formulation additionallycomprises a monohydric lower alcohol (e.g., ethanol).

In a first aspect, the formulation is propellant-free. Preferably, theformulation is foamable by manual aeration.

In a second aspect, the foamable formulation comprises at least 15% w/wDMSO. Preferably, the formulation comprises at least 25% w/w DMSO.Preferably, the formulation comprises at least 40% w/w DMSO. Preferably,the formulation comprises about 45% w/w DMSO.

In a third aspect, the active agent is a non-steroidal anti-inflammatorydrug. Preferably, the non-steroidal anti-inflammatory drug is adiclofenac salt. More preferably, the diclofenac salt is diclofenacsodium. Preferably, the non-steroidal anti-inflammatory drug isibuprofen.

In a fourth aspect, the active agent is diclofenac sodium (or,alternatively, ibuprofen) and is present at 1-10% w/w; DMSO is presentat 5-80% w/w; the monohydric lower alcohol is present at 0-50% w/w; thediol is present at 1-15% w/w; the polyalkylene glycol alkyl ether ispresent at up to 10% w/w; and q.s. water. Preferably, the polyalkyleneglycol alkyl ether is present at up to 5% w/w. More preferably, thepolyalkylene glycol alkyl ether is present at up to 2% w/w. Preferably,the monohydric lower alcohol is present at 1-50% w/w.

Alternatively, diclofenac sodium is present at a concentration selectedfrom the group of 1, 1.5, 2 and 3% w/w; DMSO is present at aconcentration selected from the group of 42, 43, 44, 45, 45.5, 46, 47,48% w/w, and fractions between; the monohydric lower alcohol is presentat 23-29% w/w; the diol is present at a concentration selected from thegroup of 9, 10, 11, 12, 13% w/w and fractions between; the polyalkyleneglycol alkyl ether is present at up to 2% w/w; and q.s. water.

Alternatively, ibuprofen is present at a concentration selected from thegroup of 3, 4, 5, 6, 7, and 8% w/w; DMSO is present at a concentrationselected from the group of 14, 16, 18, 20, 22, 24, 26, 28 and 30% w/wand percentages between; the monohydric lower alcohol is present at 0,1, 3, 5, 7, 9, 11, 13, 15, and 17% w/w; the diol is present at aconcentration selected from the group of 5, 6, 7, 8, and 9% w/w andfractions between; the polyalkylene glycol alkyl ether is present at upto 3% w/w; and q.s. water.

In a fifth aspect, the formulation comprises glycerol or any othersuitable polyol. Preferably, the formulation comprises 1-15% w/wglycerol or any other suitable polyol.

In a sixth aspect, the active agent is diclofenac sodium, and thediclofenac sodium degrades by less than 2% over the course of sixmonths. Preferably, the diclofenac sodium degrades by less than 0.04%over the course of six months at room temperature.

Alternatively, the active agent is ibuprofen, and the active agentdegrades by less than 0.6% over the course of three months at 25° C.Alternatively, the ibuprofen degrades by less than 2.0% over the courseof three months at 24° C.

In a seventh aspect, the foamable formulation has a pH between about 6.0and 10.0.

In an eighth aspect, the polyalkylene glycol alkyl ether is apolyethylene glycol alkyl ether.

In a ninth aspect, the foamable formulation comprises at most 2% w/w ofthe polyalkylene glycol alkyl ether.

In a tenth aspect, the foamable formulation comprises a steroid. Morepreferably, the steroid is cholesterol. Alternatively, the formulationcomprises at most 1% w/w of the steroid. Preferably, the formulationcomprises at most 0.5% w/w of the steroid. Still more preferably, theformulation comprises at most 0.2% w/w of the steroid. Alternatively,the formulation comprises at most 0.15% w/w of the steroid.Alternatively, the formulation comprises at most 0.05% w/w of thesteroid.

In an eleventh aspect, the foamable formulation comprises a surfactant.Preferably, the surfactant is a salt of an aryl sulfonate, alkylsulfonate, aryl sulfate, or alkyl sulfate. More preferably, the arylsulfonate salt is sodium dodecyl benzene sulfonate, and the alkylsulfate salt is sodium laureth sulfate or sodium lauryl sulphate.Alternatively, the surfactant is selected from the group of apolyalkylene glycol, a polyalkylene glycol copolymer, and aphospholipid.

Preferably, the foamable formulation comprises at most 0.5% w/w of thesurfactant. Still more preferably, the formulation comprises at most0.2% w/w of the surfactant. Alternatively, the formulation comprises atmost 0.15% w/w of the surfactant.

Preferably, the foamable formulation further comprises a pH adjustingagent. More preferably, the pH adjusting agent is sodium carbonate.

In a twelfth aspect, the foamable formulation when foamed does notcollapse to a liquid phase for at least 30 seconds at 37° C. or at skintemperature. Preferably, the formulation when foamed does not collapseto a liquid phase for at least 60 seconds at 37° C. or at skintemperature. More preferably, the formulation when foamed does notcollapse to a liquid phase for at least two minutes at 37° C. or at skintemperature. Alternatively, the formulation when foamed does notcollapse to a liquid phase for at least five minutes at 37° C. or atskin temperature.

In a thirteenth aspect, the foamable formulation when applied topicallyprovides a reduction of pain over 12 weeks. Preferably, the pain is dueto osteoarthritis or minor injury. Preferably, the formulation isapplied twice daily. Alternatively, the formulation is applied threetimes daily. Alternatively, the formulation is applied four times daily.

In a fourteenth aspect, the foamable formulation comprises a thickeningagent. Preferably, the composition comprises up to 2% (w/w) of thethickening agent. Alternatively, the viscosity of the composition is atmost about 1000 centipoise (cP). Preferably, the composition comprises0.2% w/w of the thickening agent. Still more preferably, the compositioncomprises 0.1% w/w of the thickening agent. Alternatively, the viscosityof the composition is at most about 100 cP. More preferably, theviscosity is at most about 50 cP.

In a second embodiment, the invention provides a method for treatingosteoarthritis or minor injury (e.g., minor strains, sprains, orcontusions) in a subject suffering from pain, the method comprising,consisting essentially of, or consisting of the topical administrationto an afflicted area of the subject a therapeutically effective amountof a foamable formulation, the formulation comprising: (i) DMSO; (ii) anactive agent; and (iii) a polyalkylene glycol alkyl ether. Morepreferably, the formulation comprises: (i) DMSO; (ii) an active agent;(iii) a monohydric lower alcohol; (iv) a diol; (v) a polyalkylene glycolalkyl ether; and (vi) water. Optionally, the formulation comprisesglycerol.

Alternatively, the invention provides a method for treatingosteoarthritis or minor injury (e.g., minor strains, sprains, orcontusions) in a subject suffering from pain, the method comprising,consisting essentially of, or consisting of the topical administrationto an afflicted area of the subject a therapeutically effective amountof a foamable formulation, the formulation comprising: (i) DMSO; (ii) anactive agent; and (iii) a polyalkylene glycol alkyl ether. Preferably,the formulation additionally comprises (iv) a diol; and (v) water.Optionally, the formulation comprises glycerol. Preferably, theformulation additionally comprises a monohydric lower alcohol (e.g.,ethanol).

In a first aspect of the second embodiment, the formulation ispropellant-free. Preferably, the formulation is foamable by manualaeration.

In a second aspect of the second embodiment, the foamable formulationcomprises at least 15% w/w DMSO. Preferably, the formulation comprisesat least 25% w/w DMSO. Preferably, the formulation comprises at least40% w/w DMSO. Preferably, the formulation comprises about 45% w/w DMSO.

In a third aspect of the second embodiment, the active agent is anon-steroidal anti-inflammatory drug (NSAID). Preferably, the NSAID is adiclofenac salt. More preferably, the diclofenac salt is diclofenacsodium. Preferably, the NSAID is ibuprofen.

In a fourth aspect of the second embodiment, the active agent isdiclofenac sodium (or, alternatively, ibuprofen) and is present at 1-10%w/w; DMSO is present at 5-80% w/w; monohydric lower alcohol is presentat 0-50% w/w; the diol is present at 1-15% w/w; the polyalkylene glycolalkyl ether is present at up to 10% w/w; and q.s. water. Preferably, thepolyalkylene glycol alkyl ether is present at up to 5% w/w. Morepreferably, the polyalkylene glycol alkyl ether is present at up to 2%w/w. Preferably, the monohydric lower alcohol is present at 1-50% w/w.

Alternatively, diclofenac sodium is present at a concentration selectedfrom the group of 1, 1.5, 2 and 3% w/w; DMSO is present at aconcentration selected from the group of 42, 43, 44, 45, 45.5, 46, 47,48% w/w and fractions between; the monohydric lower alcohol is presentat 23-29% w/w; the diol is present at a concentration selected from thegroup of 9, 10, 11, 12, 13% w/w and fractions between; the polyalkyleneglycol alkyl ether is present at up to 2% w/w; and q.s. water.

Alternatively, ibuprofen is present at a concentration selected from thegroup of 3, 4, 5, 6, 7, and 8% w/w; DMSO is present at a concentrationselected from the group of 14, 16, 18, 20, 22, 24, 26, 28 and 30% w/wand percentages between; the monohydric lower alcohol is present at 0,1, 3, 5, 7, 9, 11, 13, 15 and 17% w/w; the diol is present at aconcentration selected from the group of 5, 6, 7, 8, and 9% w/w andfractions between; the polyalkylene glycol alkyl ether is present at upto 3% w/w; and q.s. water.

In a fifth aspect of the second embodiment, the formulation comprises1-15% w/w glycerol or any other suitable polyol.

In a sixth aspect of the second embodiment, the active agent isdiclofenac sodium, and the diclofenac sodium degrades by less than 2%over the course of six months. Preferably, the diclofenac sodiumdegrades by less than 0.04% over the course of six months at roomtemperature.

Alternatively, the active agent is ibuprofen, and the active agentdegrades by less than 0.6% over the course of three months at 25° C.Alternatively, the ibuprofen degrades by less than 2.0% over the courseof three months at 24° C.

In a seventh aspect of the second embodiment, the foamable formulationhas a pH between about 6.0 and 10.0.

In an eighth aspect of the second embodiment, the polyalkylene glycolalkyl ether is a polyethylene glycol alkyl ether.

In a ninth aspect of the second embodiment, the foamable formulationcomprises at most 2% w/w of the polyalkylene glycol alkyl ether.

In a tenth aspect of the second embodiment, the foamable formulationcomprises a steroid. More preferably, the steroid is cholesterol.Alternatively, the formulation comprises at most 1% w/w of the steroid.Preferably, the formulation comprises at most 0.5% w/w of the steroid.Still more preferably, the formulation comprises at most 0.2% w/w of thesteroid. Alternatively, the formulation comprises at most 0.15% w/w ofthe steroid. Alternatively, the formulation comprises at most 0.05% w/wof the steroid.

In an eleventh aspect of the second embodiment, the foamable formulationcomprises a surfactant. Preferably, the surfactant is a salt of an arylsulfonate, alkyl sulfonate, aryl sulfate, or alkyl sulfate. Morepreferably, the aryl sulfonate salt is sodium dodecyl benzene sulfonate,and the alkyl sulfate is sodium laureth sulfate or sodium laurylsulfate. Alternatively, the surfactant is selected from the group of apolyalkylene glycol, a polyalkylene glycol copolymer, and aphospholipid.

Preferably, the foamable formulation comprises at most 0.5% w/w of thesurfactant. Still more preferably, the formulation comprises at most0.2% w/w of the surfactant. Alternatively, the formulation comprises atmost 0.15% w/w of the surfactant.

Preferably, the foamable formulation further comprises a pH adjustingagent. More preferably, the pH adjusting agent is sodium carbonate.

In an twelfth aspect of the second embodiment, the foamable formulationwhen foamed does not collapse to a liquid phase for at least 30 secondsat 37° C. or at skin temperature. Preferably, the formulation whenfoamed does not collapse to a liquid phase for at least 60 seconds at37° C. or at skin temperature. More preferably, the formulation whenfoamed does not collapse to a liquid phase for at least two minutes at37° C. or at skin temperature. Alternatively, the formulation whenfoamed does not collapse to a liquid phase for at least five minutes at37° C. or at skin temperature.

In a thirteenth aspect of the second embodiment, the foamableformulation when applied topically provides a reduction of pain over 12weeks. Preferably, the formulation is applied twice daily.Alternatively, the formulation is applied three times daily.Alternatively, the formulation is applied four times daily.

In a fourteenth aspect of the second embodiment, the foamableformulation comprises a thickening agent. Preferably, the compositioncomprises up to 2% (w/w) of the thickening agent. Alternatively, theviscosity of the composition is at most about 1000 centipoise (cP).Preferably, the composition comprises 0.2% w/w of the thickening agent.Still more preferably, the composition comprises 0.1% w/w of thethickening agent. Alternatively, the viscosity of the composition is atmost about 100 cP. More preferably, the viscosity is at most about 50cP.

In a third embodiment, the invention provides a dispenser comprising areservoir operably linked (e.g., in fluid communication) with a releaseassembly, wherein the reservoir contains a foamable formulation aspreviously described, and wherein the release assembly allows thefoamable formulation to be released as a foam. Preferably, the releaseassembly is a dispensing head. More preferably, the foam dispensed is aquick-breaking foam.

In a fourth embodiment, the invention provides a pressurized container,the container holding a foamable formulation as previously defined andoptionally a propellant. Preferably, a release assembly comprising anozzle or sprayer is operably linked to the container (e.g., a releaseassembly for dispensing a foam from an aerosol spray can wherein therelease assembly is in fluid communication with the spray can), whereinthe release assembly allows the foamable formulation and optionally apropellant to be released as a foam.

In a fifth embodiment, the present invention provides a method formanually foaming a formulation, the method comprising the steps of:

-   -   (i) providing a dispenser comprising a reservoir operably linked        (e.g., in fluid communication) with a release assembly (e.g.,        dispensing head),    -   (ii) filling the reservoir with a foamable formulation as        previously described, and    -   (iii) actuating the release assembly to manaully aerate the        formulation, thereby releasing a foam from the release assembly.        Preferably, the release assembly is a dispensing head that is a        pump head. Preferably the foam is a quick-breaking foam.

In a sixth embodiment, the present invention provides a topical foamprepared according the previously described method.

In a seventh embodiment, the present invention provides use of afoamable formulation in the manufacture of a medicament for thetreatment of pain wherein the formulation comprises:

-   -   (i) dimethyl sulfoxide (DMSO);    -   (ii) an active agent; and    -   (iii) a polyalkylene glycol alkyl ether.

These and other objects, aspects, and embodiments will become moreapparent when read with the following detailed description and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates foams produced by manual shaking of the Example 3formulations (Table 3). The picture was taken immediately after manualshaking for 30 sec.

FIG. 2 illustrates foams produced by manual shaking of the Example 3formulations (Table 3). The picture was taken 2 minutes after manualshaking for 30 sec.

FIG. 3 illustrates foams produced by manual shaking of the Example 3formulations (Table 3). The picture was taken 5 minutes after manualshaking for 30 sec.

FIG. 4 illustrates foams produced by manual shaking of the Example 3formulations (Table 3). The picture was taken 35 minutes after manualshaking for 30 sec.

FIG. 5 illustrates foams produced by manual shaking of the Example 3formulations (Table 3). The picture was taken 1 hour after manualshaking for 30 sec.

FIG. 6 illustrates foams produced by manual shaking of the Example 3formulations (Table 3). The picture was taken 2 hours after manualshaking for 30 sec.

FIG. 7 illustrates foams produced by manual shaking of the Example 3formulations (Table 3). The picture was taken 3 hours after manualshaking for 30 sec.

FIG. 8 illustrates foams produced by manual shaking of the Example 3formulations (Table 3). The picture was taken 24 hours after manualshaking for 30 sec.

FIG. 9 illustrates the foam produced by dispensing Formulation I(Example 3) when sprayed using a hand dispenser. The picture was takenimmediately after dispensing the foam.

FIG. 10 illustrates the foam produced by dispensing Formulation I(Example 3) when sprayed using a hand dispenser. The picture was taken 2minutes after dispensing the foam.

FIG. 11 illustrates the foam height produced by shaking FormulationP100118-01 for 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60,64, 68, 72, 76 and 80 seconds.

FIG. 12 illustrates the foam height produced by shaking FormulationP100118-02 for 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60,64, 68, 72, 76 and 80 seconds.

FIG. 13 illustrates the foam height produced by shaking FormulationP100118-03 for 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60,64, 68, 72, 76 and 80 seconds.

FIG. 14 illustrates the foam height produced by shaking FormulationP100118-04 for 4, 8, 12, 16, 20, 24, 28, 32, 36 and 40 seconds.

FIG. 15 illustrates the foam height produced by shaking FormulationP100118-05 for 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60,64, 68, 72, 76 and 80 seconds.

FIG. 16 illustrates the foam height produced by shaking FormulationP100118-06 for 4, 8, 12, 16, 20, 24, 28, 32, 36 and 40 seconds.

FIG. 17 illustrates the foam height produced by shaking FormulationP100118-07 for 4, 8, 12, 16, 20, 24, 28, 32, 36 and 40 seconds.

FIG. 18 illustrates the foam height produced by shaking FormulationsP100118-01 to P100118-07 after 30 seconds of shaking.

FIG. 19 illustrates the foam collapsibility of a series of topicalformulations (P100223) at 0, 5 and 30 minutes after shaking.

FIG. 20 illustrates the foam collapsibility of a series of topicalformulations (P100223) after 30 seconds of shaking.

FIG. 21 illustrates the foam collapsibility of a series of topicalformulations (P100223) at 0, 5 and 30 minutes after shaking.

FIG. 22 illustrates the foam collapsibility of a series of topicalformulations (P100223) after 30 seconds of shaking.

FIG. 23 illustrates diclofenac sodium permeation through dermatomedporcine skin from a series of topical formulations (P100118) at 4 and 24hours after application.

FIG. 24 illustrates diclofenac sodium permeation through Dermatomedprocine skin from a series of topical formulations (P100223) at 4, 20and 24 hours after application.

FIG. 25 illustrates diclofenac sodium permeation through dermatomedporcine skin from a series of topical formulations (P100223) at 4, 20and 24 hours after application.

FIG. 26 illustrates diclofenac sodium permeation through human cadaverskin from a series of topical formulations (P100201) at 4, 8, 12, 20 and24 hours after application.

FIG. 27 illustrates the foam stability of a series of formulations(P100310) over two minutes following dispensing from a Rexam M3 foameron the back of a volunteer's hand.

FIG. 28 illustrates the foam quality of P100310 sSeries formulationsafter spreading.

FIG. 29 illustrates diclofenac sodium permeation data for P100310 seriesformulations (Franz diffusion cell, human cadaver skin).

FIG. 30 illustrates foam stability assessed by the vortex mixing methodusing P100323 series formulations after 30 seconds of vortex mixing.

FIG. 31 illustrates in vitro diclofenac delivery from P100323Formulations (Franz diffusion cells, human cadaver skin).

FIG. 32 illustrates foam stability assessed by the vortex mixing methodusing P100312 series formulations after 30 seconds of vortex mixing.

FIG. 33 illustrates diclofenac sodium permeation data for P100312 seriesformulations (Franz diffusion cell, human cadaver skin).

FIG. 34 illustrates foam stability assessed by the vortex mixing methodusing P100325 series formulations after 30 seconds of vortex mixing.

FIG. 35 illustrates diclofenac sodium permeation data for P100325 seriesformulations (Franz diffusion cell, human cadaver skin).

FIG. 36 illustrates foam stability assessed by the vortex mixing methodusing P100324 series formulations after 30 seconds of vortex mixing.

FIG. 37 illustrates diclofenac sodium permeation data for P100324 seriesformulations (Franz diffusion cell, human cadaver skin).

FIG. 38 illustrates a comparison of the diclofenac delivery among fourselected formulations (P100310).

FIG. 39 illustrates general properties of the Rexam M3 foaming head.

FIG. 40 illustrates the structure of the Rexam M3 foaming head.

FIG. 41 illustrates the material components of the Rexam M3 foaminghead.

FIG. 42 illustrates the foam collapse for formulation P100310-01 afterbeing dispensed from a Rexam M3 foamer and after being rubbed on anapplication site.

FIG. 43 illustrates the foam collapse for formulation P100310-02 afterbeing dispensed from a Rexam M3 foamer and after being rubbed on anapplication site.

FIG. 44 illustrates the foam collapse for formulation P100310-03 afterbeing dispensed from a Rexam M3 foamer and after being rubbed on anapplication site.

FIG. 45 illustrates the foam collapse for formulation P100310-04 afterbeing dispensed from a Rexam M3 foamer and after being rubbed on anapplication site.

FIG. 46 illustrates the foam collapse for formulation P100310-05 afterbeing dispensed from a Rexam M3 foamer and after being rubbed on anapplication site.

FIG. 47 illustrates the foam collapse for formulation P100310-06 afterbeing dispensed from a Rexam M3 foamer and after being rubbed on anapplication site.

FIG. 48 illustrates the foam collapse for formulation P100310-07 afterbeing dispensed from a Rexam M3 foamer and after being rubbed on anapplication site.

FIG. 49 illustrates the foam collapse for formulation P100310-08 afterbeing dispensed from a Rexam M3 foamer and after being rubbed on anapplication site.

FIG. 50 illustrates the foam collapse for formulation P100310-09 afterbeing dispensed from a Rexam M3 foamer and after being rubbed on anapplication site.

FIG. 51 illustrates the foam collapse for formulation P100312-01 afterbeing dispensed from a Rexam M3 foamer and after being rubbed on anapplication site.

FIG. 52 illustrates the foam collapse for formulation P100312-03 afterbeing dispensed from a Rexam M3 foamer and after being rubbed on anapplication site.

FIG. 53 illustrates the foam collapse for formulation P100312-04 afterbeing dispensed from a Rexam M3 foamer and after being rubbed on anapplication site.

FIG. 54 illustrates the foam collapse for formulation P100312-05 afterbeing dispensed from a Rexam M3 foamer and after being rubbed on anapplication site.

FIG. 55 illustrates the foam collapse for formulation P100312-06 afterbeing dispensed from a Rexam M3 foamer and after being rubbed on anapplication site.

FIG. 56 illustrates the effect of sodium carbonate on the delivery ofibuprofen from foam formulations.

FIG. 57 illustrates the effect of sodium carbonate in presence ofthickening agent, and reduction of total surfactant on the delivery ofibuprofen.

FIG. 58 illustrates the effect of addition of Brij 78, increasedethanol, and removal of glycerin on delivery of ibuprofen.

FIG. 59 illustrates the effect of anionic surfactant ratio and totalsurfactant concentration on delivery of ibuprofen.

FIG. 60 illustrates the effect of non-ionic surfactant concentration onthe delivery of ibuprofen.

FIG. 61 illustrates the effect of reduced surfactant concentration andsurfactant type on the delivery of ibuprofen.

FIG. 62 illustrates the effect of non-ionic surfactants on delivery ofibuprofen.

FIG. 63 illustrates the effect of Brij 78 levels on the delivery ofibuprofen.

FIG. 64 illustrates the effect of cholesterol levels on the delivery ofibuprofen from DMSO based formulations.

FIG. 65 illustrates the effect of water-based formulations on thedelivery of ibuprofen.

FIG. 66 illustrates the effect of thickening agents and Poloxamer 407 onthe delivery of ibuprofen from water based formulations.

FIG. 67 illustrates the effect of varying DMSO content on the deliveryof ibuprofen.

FIG. 68 illustrates the effect of varying ethanol and glycerin levels onthe delivery of ibuprofen.)

FIG. 69 illustrates ibuprofen permeability from formulations selectedfor stability studies.

FIG. 70 illustrates ibuprofen permeability from formulations selectedfor stability studies.

FIG. 71 illustrates ibuprofen permeability from formulations selectedfor stability studies.

FIG. 72 illustrates the qualitative properties of the ibuprofen testformulations (foam/no foam/precipitate).

FIG. 73 illustrates the foam produced from formulation 1 (F110128-1).

FIG. 74 illustrates the foam produced from formulation 2 (F110128-2).

FIG. 75 illustrates the foam produced from formulation 3 (F110128-3).

FIG. 76 illustrates the foam produced from formulation 4 (F110131-1).

FIG. 77 illustrates the foam produced from formulation 5 (F110131-2).

FIG. 78 illustrates the foam produced from formulation 6 (F110131-3).

FIG. 79 illustrates the foam produced from formulation 7 (F110131-4).

FIG. 80 illustrates the foam produced from formulation 8 (F110131-5).

FIG. 81 illustrates the foam produced from formulation 9 (F110131-6).

FIG. 82 illustrates the foam produced from formulation 10 (F110201-1).

FIG. 83 illustrates the foam produced from formulation 11 (F110201-2).

FIG. 84 illustrates the foam produced from formulation 12 (F110201-3).

FIG. 85 illustrates the foam produced from formulation 13 (F110203-1).

FIG. 86 illustrates the foam produced from formulation 14 (F110203-2).

FIG. 87 illustrates the foam produced from formulation 15 (F110203-3).

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions of Terms

The terms “a,” “an,” or “the” as used herein not only includes aspectswith one member, but also includes aspects with more than one member.For example, an embodiment including “a cellulosic thickening agent anda lower monohydric alcohol” should be understood to present certainaspects with at least a second cellulosic thickening agents, at least asecond lower monohydric alcohol, or both. An embodiment including “anactive agent” should be understood to present certain aspects with atleast a second active agent, which may be of a different class (e.g., anon-steroidal anti-inflammatory drug with an anti-inflammatory steroidor a local anesthetic).

The term “about” as used herein to modify a numerical value indicates adefined range around that value. If “X” were the value, “about X” wouldgenerally indicate a value from 0.95X to 1.05X. Any reference to “aboutX” specifically indicates at least the values X, 0.95X, 0.96X, 0.97X,0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus, “about X” isintended to teach and provide written description support for a claimlimitation of, e.g., “0.98X.” When the quantity “X” only includeswhole-integer values (e.g., “X carbons”), “about X” indicates from (X−1)to (X+1). In this case, “about X” as used herein specifically indicatesat least the values X, X−1, and X+1.

When “about” is applied to the beginning of a numerical range, itapplies to both ends of the range. Thus, “from about 5 to 20%” isequivalent to “from about 5% to about 20%.” When “about” is applied tothe first value of a set of values, it applies to all values in thatset. Thus, “about 7, 9, or 11%” is equivalent to “about 7%, about 9%, orabout 11%.”

In compositions comprising an “additional” or “second” component, thesecond component as used herein is chemically different from the othercomponents or first component. A “third” component is different from theother, first, and second components, and further enumerated or“additional” components are similarly different.

“Agent” as used herein indicates a compound or mixture of compoundsthat, when added to a pharmaceutical composition, tend to produce aparticular effect on the composition's properties. For example, acomposition comprising a thickening agent is likely to be more viscousthan an otherwise identical comparative composition that lacks thethickening agent.

As used herein, the phrase “effective amount” or “effective dose” meansan amount sufficient to achieve the desired result and accordingly willdepend on the ingredient and its desired result. Nonetheless, once thedesired effect is known, determining the effective amount is within theskill of a person skilled in the art.

“Enhancement ratio” (“ER”) as used herein is the ratio of a test result(e.g., ug/cm² accumulated dose of product) from a formulation comprisingan active to the corresponding test result from a control compositioncomprising the same active at the same concentration in the formulation.

In general, the “error bars” on the graphs represent the standard errorof the mean value, whereas the top of the solid, shaded bar represents asingle data value, which is the mean value of the distribution of datavalues.

“Finite dosing” as used herein generally includes an application of alimited reservoir of an active agent. The active agent in the reservoiris depleted with time, leading to a decrease of the absorption rateafter a maximum rate is reached.

“Formulation,” “pharmaceutical composition,” and “composition” as usedinterchangeably herein are equivalent terms referring to a compositionof matter for pharmaceutical use.

“Monohydric alcohol” as used herein includes straight- or branched-chainalkyl alcohols with a single hydroxyl group. Representative monohydricalcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol,t-butanol, n-pentanol, 3-pentanol, 2-methoxyethanol,2-(2-ethoxyethoxy)ethanol, olelyl alcohol, and the like.

The term “or” as used herein should in general be construednon-exclusively. For example, an embodiment of “a composition comprisingA or B” would typically present an aspect with a composition comprisingboth A and B. “Or” should, however, be construed to exclude thoseaspects presented that cannot be combined without contradiction (e.g., acomposition pH that is between 9 and 10 or between 7 and 8).

“Penetration enhancer”, “molecular penetration enhancer” or “MPE™” asused herein includes an agent or a combination of agents that improvesthe transport of molecules such as a pharmaceutically or cosmeticallyactive agent into or through a natural membrane such as skin or nail.Various conditions may occur at different sites in the body, either inthe skin or below the skin, creating a need to target delivery ofcompounds. For example, in a treatment for osteoarthritis, delivery ofthe active agent to the underlying tissues surrounding the joint may benecessary to achieve therapeutic benefit. A molecular penetrationenhancer may be used to assist in the delivery of an active agent i)directly into the skin or nail; ii) locally, or regionally, intotissue(s) underlying the skin or nail; or iii) indirectly via systemicdistribution to the site of the disease. If systemic distribution of anactive agent (e.g., ibuprofen) would be likely to produce side effects,a molecular penetration enhancer is preferably selected to maximizedirect delivery and to minimize systemic distribution. A molecularpenetration enhancer may be a pure substance or may comprise, consistessentially of, or consist of a mixture of different chemical entities.

The term “pH adjusting agent” as used herein refers to a compound addedto the compositions of the present application for the purpose ofchanging the pH of the composition. Examples of such agents includepharmaceutically acceptable acids, pharmaceutically acceptable bases,and pharmaceutically acceptable buffers.

The term “pharmaceutically acceptable” means compatible with thetreatment of animals, and in particular, humans.

The term “pharmaceutically acceptable salt” means a pharmaceuticallyacceptable acid addition salt or a pharmaceutically acceptable basicaddition salt. The formation of a desired compound salt is achievedusing standard techniques. For example, the neutral compound is treatedwith an acid or base in a suitable solvent and the formed salt isisolated by filtration, extraction, or any other suitable method.

The term “subject” as used herein includes all members of the animalkingdom, preferably mammals, and most preferably, humans.

“Surfactant” as used herein includes a surface-active agent. Surfactantsreduce the surface tension of a solvent in which they are dissolved.

“Thickening agent” as used herein includes an agent or combination ofagents that increases the viscosity of a composition. A thickening agentmay be a pure substance, or it may comprise, consist essentially of, orconsist of a mixture of different chemical entities. Exemplarythickening agents include cellulose polymers, carbomer polymers,carbomer derivatives, cellulose derivatives, polyvinyl alcohol,poloxamers, polysaccharides, and the like, as well as mixtures thereof.

“Topical formulation” as used herein includes a composition that issuitable for topical application to the skin, a nail, or a mucosa. Atopical formulation may, for example, be used to confer a therapeutic orcosmetic benefit to its user. Specific topical formulations can be usedfor local, regional, or transdermal application of substances.

“Transdermal” as used herein includes a process that occurs through theskin. The terms “transdermal,” “percutaneous,” and “transcutaneous” canbe used interchangeably. In certain embodiments, “transdermal” may alsoinclude epicutaneous.

“Transdermal application” as used herein includes administration throughthe skin. Transdermal application can be used for systemic delivery ofan active agent; however, it is also useful for delivery of an activeagent to tissues underlying the skin with minimal systemic absorption.In certain embodiments, “transdermal application” may also includeepicutaneous application.

The term “treating” or “treatment” as used herein (and as wellunderstood in the art) means an approach for obtaining beneficial ordesired results in a subject's condition, including clinical results.Beneficial or desired clinical results can include, but are not limitedto, alleviation or amelioration of one or more symptoms or conditions,diminishment of the extent of a disease, stabilizing (i.e., notworsening) the state of disease, prevention of a disease's transmissionor spread, delaying or slowing of disease progression, amelioration orpalliation of the disease state, diminishment of the reoccurrence ofdisease, and remission, whether partial or total and whether detectableor undetectable.

“Treating” and “treatment” as used herein also include prophylactictreatment. Treatment methods comprise administering to a subject atherapeutically effective amount of an active agent. The administeringstep may consist of a single administration or may comprise a series ofadministrations. The length of the treatment period depends on a varietyof factors, such as the severity of the condition, the age of thepatient, the concentration of active agent, the activity of thecompositions used in the treatment, or a combination thereof. It willalso be appreciated that the effective dosage of an agent used for thetreatment or prophylaxis may increase or decrease over the course of aparticular treatment or prophylaxis regime. Changes in dosage may resultand become apparent by standard diagnostic assays known in the art. Insome instances, chronic administration may be required. For example, thecompositions are administered to the subject in an amount and for aduration sufficient to treat the patient.

The prefix “micro” as used herein can be alternatively abbreviated as“μ” or “u.” For example, micrograms are typically abbreviated as μg, butcan alternatively be abbreviated as “ug.”

The term “w/w” or “wt/wt” means a percentage expressed in terms of theweight of the ingredient or agent over the total weight of thecomposition multiplied by 100.

II. Embodiments

A. Active Agent

In one preferred aspect, the active agent is an anti-inflammatory agent.More preferably, the agent is a non-steroidal anti-inflammatory drug(NSAID). Preferably, the agent is a diclofenac salt. More preferably,the diclofenac salt is diclofenac sodium. An embodiment including “anactive agent” should be understood to present certain aspects with atleast a second active agent, which may be the same class or a differentclass (e.g., a non-steroidal anti-inflammatory drug with ananti-inflammatory steroid or a local anesthetic).

Non-limiting examples of NSAIDs include acetic acid derivatives such asindomethacin, sulindac, etodolac, and diclofenac; propionic acidderivatives such as ibuprofen, naproxen, fenoprofen, ketoprofen,fluriprofen, and oxaprozin; coxibs such as celecoxib, rofecoxib,valdecoxib, parecoxib, lumiracoxib, and etoricoxib; fenamic acidderivatives such as mefenamic acid, meclofenamic acid, flufenamic acid,and tolfenamic acid; enolic acid derivatives such as piroxicam,meloxicam, tenoxicam, droxicam, and isoxicam; and the compounds'pharmaceutically acceptable salts such as diclofenac sodium, naproxensodium, and diclofenac potassium. Acetic acid derivatives, coxibs, andtheir pharmaceutically acceptable salts are preferred.

Other NSAIDs include aspirin, salicylic acid, diflunisal, etodolac,nabumetone, salsalate, bromfenac, ketorolac, tolmetin, and theirpharmaceutically acceptable salts. Also included are dexibuprofen (i.e.,(S)-+-ibuprofen) or ibuprofen that is enantiomerically enriched with thedexibuprofen enantiomer.

B. Dimethyl Sulfoxide (DMSO)

In one preferred aspect, the compositions and formulations include DMSO.The DMSO may be present in an amount of 5% to 80% w/w. Preferably, DMSOis present in an amount ranging from about 5-30% w/w, about 10-40% w/w,about 15-50% w/w, about 20-60% w/w, about 25-70% w/w, or about 30-80%w/w. Alternatively, a clinically effective amount of DMSO may range from5% to 60% w/w. Preferably, DMSO is present in an amount of at least 15%w/w. More preferably, DMSO is present in an amount of at least 25% w/w.Still more preferably, DMSO is present in an amount of at least 45% w/w.In a particular embodiment of the invention, DMSO is used at aconcentration of about 12 to 48% w/w. Preferably, DMSO is used at aconcentration such as 42, 43, 44, 45, 45, 46, 47 and 48% w/w as well asall fractions between such as 42.5, 43.5 44.5, 45.5, and the like.Alternatively, DMSO is used at a concentration such as 14, 16, 18, 20,22, 24, 26, 28 and 30% w/w as well as all percentages between.

DMSO is a polar aprotic solvent characterized as having low surfacetension. Producing a foamable formulation comprising DMSO (or highconcentration DMSO liquids) is difficult, requiring extensiveexperimentation and analyses. As discussed below, the constituentsrequired to achieve a foamable formulation are not readily discernable.In fact, the majority of compounds tested had less than desirablequalities for producing a foamable DMSO-containing formulation. Despitethis, polyethylene glycol alkyl ethers (e.g., Brij 30, Brij 78, Brij 90,Brij 98, and the like) provided surprisingly good results. In addition,altering the ratio of DMSO to ethanol improved foam quality. Best foamswere produced at a ratio of 0:70 to 20:60 (EtOH:DMSO).

C. Lower Alcohols and Diols

In one preferred aspect, the compositions and formulations include alower alcohol. More preferably, the lower alcohol is a monohydric loweralcohol, and still more preferably, the lower alcohol is selected from aC₁ to C₆ alkanol, such as methanol, ethanol, propanol, isopropanol,butanol, isobutanol, sec-butanol, pentanol, and the like, as well as amixture thereof. Ethanol is preferred.

In certain aspects the composition includes about 0% to 60% (w/w) orabout 1 to 50% (w/w) of the lower alcohol (e.g., ethanol). In otheraspects, the formulations include about 5, 10, 15, 20, 22, 23, 25, 3032, 33, 35, 36, 40, 41, 42, 45, 50, 55, or 60% (w/w) of a lower alcohol.More preferably, the composition comprises from about 5% to 25% (w/w) ofa lower alcohol, such as about 5, 6, 7, 8, 9, 10, 11, 11.2, 12, 13, 15,18, 20, 22, 23, or 25%. Alternatively, the composition comprises fromabout 1 to 5%, about 1 to 12%, about 5 to 15%, about 5 to 22.5%, about10 to 23%, about 15 to 30%, about 20 to 40%, about 25 to 50%, about 35to 50%, about 35 to 60% (w/w) of a lower alcohol. Alternatively, thecomposition comprises about 22, 22.5, 23, 25, 30, 32, 32.5, 33, 35,35.5, 36, 39, 39.5, 40, 41, 41.7, 42, or 50% (w/w) of a lower alcohol.

In another aspect, the formulations include a diol. Suitable diolsinclude, but are not limited to, propylene glycol, butanediol,butynediol, pentanediol, hexanediol, octanediol, neopentyl glycol,2-methyl-1,3-propanediol, diethylene glycol, triethylene glycol,tetraethylene glycol, dipropylene glycol, dibutylene glycol, propyleneglycol, and the like, as well as a mixture thereof. In one aspect, theformulation comprises about 0% to 15% (w/w) of propylene glycol, andpreferably about 0 to 8%. In certain preferred aspects, the diol is aglycol, such as ethylene glycol, propylene glycol, or a mixture thereof.More preferably, the diol is propylene glycol.

In still another aspect, the formulation includes at least two alcohols.Preferably, the formulation includes a monohydric alcohol and a diol.More preferably, the monohydric alcohol is ethanol. Alternatively, thediol is propylene glycol. Still more preferably, the monohydric alcoholis ethanol, and the diol is propylene glycol.

D. Polyalkylene Glycol Alkyl Ether

In one preferred aspect, the composition includes at least onepharmaceutically acceptable surfactant that is a polyalkylene glycolalkyl ether. The polyalkylene glycol alkyl ether may be present at up toabout 5% w/w, such as about 0.1, 0.15, 0.2, 0.3, 0.4, 0.5, 1.0, 1.5, 2,2.5, 3, 3.5, 4, 4.5 or 5% w/w. More preferably, the polyalkylene glycolalkyl ether is present at up to about 3% w/w, such as about 0.1, 0.15,0.2, 0.3, 0.4, 0.5, 1.0, 1.25, 1.5, 1.75, 2.0; 2.25, 2.5, 2.75 or 3%w/w.

Preferably, the composition includes a polyalkyene glycol alkyl ether;more preferably, a polyalkylene glycol alkyl ether such as apolypropylene oxide alkyl ether or a polyethylene glycol alkyl ether.Some non-limiting examples of polyalkylene glycol alkyl ethers includepoly(oxyethylene) cetyl ether, poly(oxyethylene) palmityl ether,polyethylene oxide hexadecyl ether, polyethylene glycol cetyl ether,Brij 30, Brij 38, Brij 52, Brij 56, Brij 58, Brij 78, Brij 98, Brij 700,Brij 700P, Brij 721, and Brij W1. Preferably, the polyalkylene glycolalkyl ether is a combination of Brij 30 and Brij 78. The Brij group ofnon-ionic surfactants are particularly preferred for their surprisingeffectiveness at producing foams from formulations including largeproportions of DMSO. Further, these surfactants are particularlyeffective in producing a foamable formulation in the absence of apropellant.

Other non-limiting examples include members of the class of alkyl ethernonionic surfactants with two to 100 alkylene glycol repeat units intheir polyalkylene glycol polymeric chains. Preferably, the alkyl groupis derived from a fatty acid alcohol. Preferably, the polyalkeneneglycol is polyethylene glycol.

The composition may include a polyalkylene glycol block co-polymer suchas Poloxamer 188 or Poloxamer 407. Alternatively, the formulationincludes a phospholipid. These components may be preferred for use witha foamable formulation that requires use of a propellant, such asoctane, butane or isopentane, for conversion to a foam or for stabilityof the resulting foam.

D. Surfactants

In one aspect, the composition may include one or more additionalnonionic, cationic, anionic, and/or zwitterionic surfactants. The one ormore surfactants may be present at about 0.1% or 0.15% to 10% w/w, suchas about 0.1, 0.15, 0.2, 0.3, 0.4, 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 7, 8, 9or 10% w/w.

1. Nonionic Surfactants

Non-limiting examples of nonionic surfactants include polysorbates, suchas polysorbate 20 (Tween 20), Tween 40, Tween 60, and Tween 80;poly(oxyethylene) (POE) fatty acid esters, such as Myrj 45, Myrj 49,Myrj 52 and Myrj 59; sucrose esters; partial esters of sorbitol and itsanhydrides, such as sorbitan monolaurate; mono or diglycerides; andisoceteth-20.

Other non-limiting examples include members of the class of alkyl esternonionic surfactants with 8 to 100 alkylene glycol repeat units in theirpolyalkylene glycol polymeric chains (e.g., 8, 40, 50, or 100).Preferably, the ester group is derived from a fatty acid. Preferably,the polyalkenene glycol is polyethylene glycol.

Other nonionic surfactants include, but are not limited to, cetomacrogol1000, cetostearyl alcohol, cetyl alcohol, cocoamide diethanolamine,cocoamide monoethanolamine, decyl glucoside, glyceryl laurate, laurylglucoside, polyoxyethylene ethers of fatty acids such as cetyl alcoholor stearyl alcohol, narrow-range ethoxylates, octyl glucoside, oleylalcohol, poloxamers, polyethylene glycol, sorbitan monolaurate,polyoxyethylene sorbitan monolaurate, sorbitan dioleate, sorbitantrilaurate, sorbitan monopalmitate, polyoxyethylene (20) sorbitanmonopalmitate, sorbitan monostearate, sorbitan tristearate,polyoxyethylene (20) sorbitan monostearate, sorbitan monooleate,sorbitan trioleate, polyoxyethylene sorbitan monooleate, stearylalcohol, sucrose coconut fatty ester mixtures, glycerin monolaurate, andsucrose monolaurate.

Still other non-ionic surfactants include, but are not limited to, fattyacid diesters, polyethylene glycol glycerol fatty acid esters,alcohol-oil transesterification products, polyglycerized fatty acids,sterol and sterol derivatives, polyethylene glycol alkyl ethers, sugaresters, polyethylene glycol alkyl phenols,polyoxyethylene-polyoxypropylene block copolymers, sorbitan fatty acidesters and lower alcohol fatty acid esters.

2. Cationic Surfactants

Non-limiting examples of cationic surfactants include octyltrimethylammonium salts, cetyl trimethyl ammonium salts, stearyltrimethyl ammonium salts, benzyl trimethyl ammonium salts, alkylamines,alkylimidazoles, ethoxylated amines, non-amphoteric quaternarysurfactants, esterquats, and a mixture thereof. Quaternary surfactantscontain at least one nitrogen atom, which is covalently bonded to fouralkyl or aryl groups.

Cationic surfactants include, but are not limited to, non-amphotericquaternary ammonium compounds, in particular benzyltrialkyl ammoniumchlorides or bromides, e.g., benzyl dimethylstearyl ammonium chloride;alkyl trialkyl ammonium salts, e.g., cetyl trimethyl ammonium chlorideor bromide, alkyl dimethylhydroxyethyl ammonium chloride or bromide,dialkyl dimethyl ammonium chloride or bromide, and alkylamideethyltrimethyl ammonium ether sulfates; alkylpyridinium salts, e.g.,lauryl or cetyl pyrimidinium chloride; N,N′-dialkylimidazolinederivatives; compounds having cationic character, such as amine oxides,e.g., alkyl dimethylamine oxides or alkylaminoethyl dimethylamineoxides; and the like.

3. Anionic Surfactants

Non-limiting examples of anionic surfactants include alkyl sulfates,e.g., sodium, ammonium or triethylammonium (TEA) lauryl sulfate orlaureth sulfate; acylamino acids (and their salts), such as acylglutamates, e.g., sodium acyl glutamate, di-TEA palmitoyl aspartate, andsodium caprylic/capric glutamate; acyl peptides, e.g.,palmitoyl-hydrolyzed milk protein, sodium cocoyl-hydrolyzed soya proteinand sodium/potassium cocoyl-hydrolyzed collagen; sarcosinates, e.g.,myristoyl sarcosin, TEA-lauroyl sarcosinate, sodium lauroyl sarcosinateand sodium cocoyl sarcosinate; taurates, e.g., sodium lauroyl taurateand sodium methylcocoyl taurate; acyl lactylates, lauroyl lactylate,caproyl lactylate; and alaninates; and the like.

Other anionic surfactants include carboxylic acids and derivatives, suchas carboxylic acids, e.g., lauric acid, aluminum stearate, magnesiumalkanolate, and zinc undecylenate; ester carboxylic acids, e.g., calciumand sodium stearoyl lactylates, laureth-6 citrate, and sodium PEG-4lauramide carboxylate; ether carboxylic acids, e.g., sodium laureth-13carboxylate, and sodium PEG-6 cocoamide carboxylate; and the like.

Other anionic surfactants include esters of phosphoric acid and salts,e.g., dilaureth-4 phosphate.

Other anionic surfactants include sulfonic acids and salts, such as acylisethionate, e.g., sodium-ammoniumcocoyl isethionate, alkylarylsulfonates; alkyl sulfonates, e.g., sodium coco monoglyceride sulfate,sodium C₁₂₋₁₄ olefin-sulfonate, sodium lauryl sulfoacetate and magnesiumPEG-3 cocamide sulfate; sulfosuccinates, e.g., dioctyl sodiumsulfosuccinate, disodium laureth sulfosuccinate, disodium laurylsulfosuccinate, disodium undecylenamido-MEA-sulfosuccinate, and PEG-5lauryl citrate sulfosuccinate; esters of sulfuric acid, such as alkylether sulfate, e.g., sodium, ammonium, magnesium, MIPA, TIPA, laurethsulfate, lauryl sulfate, sodium myreth sulfate and sodium C₁₂₋₁₃ parethsulfate; and the like.

4. Zwitterionic Surfactants

In one aspect, the composition comprises a zwitterionic surfactant or acharged derivative thereof. In one aspect, the zwitterionic surfactantor charged derivative thereof is selected from the group of disodiumcocoamphodiacetate, sodium cocoamphodiacetate, cocoamidopropyl betaine,and a mixture thereof.

Other zwitterionic surfactants or charged derivatives thereof include,but are not limited to, amino acids such as β-N-alkylaminopropionicacids, aminopropyl alkylglutamide, alkylaminopropionic acid, sodiumalkylimidodipropionate, dihydroxyethyl alkyl glycinate, andlauroamphocarboxyglycinate; imino acids such asN-alkyl-β-iminodipropionic acids; imidazoline derivatives that are notN,N′-dialkylated; quaternary ammonium amino acid sulfobetaines such asalkyl amidopropyl hydroxysultaines, cocoamidopropyl hydroxysultaine,sodium cocoamphohydroxypropyl sulfonate, or sodiumcapryloamphohydroxypropyl sulfonate; quaternary ammonium amino acidbetaines, e.g., dodecyl betaine; alkyl amidopropyl betaines such ascocoamidopropyl betaine; alkyl dimethyl betaines; phospholipids such aslecithin; acyl dialkyl ethylenediamines, e.g., sodium acyl amphoacetate,disodium acyl amphodipropionate, disodium alkyl amphodiacetate, sodiumacyl amphohydroxypropyl sulfonate, disodium acyl amphodiacetate, andsodium acyl amphopropionate; a salt of cocamphodiactetate, such assodium cocamphodiacetate; and the like.

E. Water

In certain aspects, the compositions include water. Preferably, water ispresent from about 5% to 75% (w/w) such as about 5, 6, 7, 8, 9, 10, 11,12, 12.5, 13, 14, 15, 16, 16.6, 17, 17.5, 18, 18.5, 19, 20, 21, 22, 23,24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 or 75% by weight. Preferably,water is present from about 5% to 25% (w/w). More preferably, thecomposition includes from about 5 to 10%, about 10 to 20%, about 10 to15%, about 15 to 20%, about 20 to 30%, about 30 to 40%, about 40 to 50%,about 50 to 60%, about 60 to 70%, or about 70 to 75% (w/w) water.Alternatively, the mixture includes about 8, 9, 10, 12, 12.5, 13, 16,16.6, or 17% (w/w) or q.s. water.

F. Steroids

In another aspect, the composition may include a steroid. Non-limitingexamples include cholesterol and derivatives thereof. Preferably, theformulation comprises at most 1% (w/w) of the steroid. More preferably,the formulation comprises at most 0.5% (w/w) of the steroid. Still morepreferably, the formulation comprises at most 0.2% (w/w) of the steroid.Alternatively, the formulation comprises at most 0.15% w/w of thesteroid; more preferably, at most 0.05% w/w of the steroid.

Steroids may be included in the composition to enhance or improve foamstability. In particular, where surfactant-type components in theformulation result in short-lived foams, a steroid may be added toextend the life of the foam. As discussed below, measureable aspects offoam stability include foam formation, foam height and foamcollapsibility.

Procedurally, the surfactant (e.g., Brij) and steroid may be added tothe formulation by vortexing and heating. Alternately, the surfactantmay be added into the hydroalchoholic fraction and the steroid into theremaining organic part, and the resulting phases then combined. This isthe preferred process as it does not require heating.

G. Emollients

Emollients can optionally be added to the foamable formulations of theinvention so that the formulations can maintain or increase the moisturecontent of the stratum corneum when the composition is applied (e.g.,the skin of the knee). Emollients may be added to the formulations inaddition to the components already described, which may also aid inmaintaining or improving the skin condition of the user. The use ofemollients in a foamable composition is discussed in U.S. Pat. No.7,651,990.

In one aspect, added emollients are included in the compositions of theinvention at a concentration between about 0.1 and 20% w/w. In anotheraspect, the added emollient can be present in the composition at aconcentration between about 0.5% and 10% w/w. In still another aspect,the emollient concentration can be between about 1% and 5% w/w.

Emollients are generally separated into two broad classes based on theirfunction. The first class of emollients functions by forming anocclusive barrier to prevent water evaporation from the stratum corneum.The second class of emollients penetrate into the stratum corneum andphysically bind water to prevent evaporation. The first class ofemollients is subdivided into compounds which are waxes at roomtemperature and compounds which are liquid oils. The second class ofemollients includes those which are water soluble and are often referredto as humectants.

Suitable emollients may be selected from any of the classes known in theart. A general list of useful emollients appears, for example, in U.S.Pat. No. 4,478,853 and in EP patent application 0 522 624A1 as well asin the CTFA Cosmetic Ingredient Handbook published by The Cosmetic,Toiletry, and Fragrance Association, Wash. D.C. (1992) under thelistings “Skin Conditioning agents,” “emollients,” “humectants,”“miscellaneous” and “occlusive.”

In some aspects, emollients may be chosen from the followingnon-limiting list of general emollients, occlusive emollients, andhumectants. Examples of general emollients include short-chain alkyl oraryl esters (C₁-C₇) of long-chain straight- or branched-chain alkyl oralkenyl alcohols or acids (C₉-C₃₂) and their polyethoxylatedderivatives; short-chain alkyl or aryl esters (C₁-C₇) of C₄-C₁₂ diacidsor diols optionally substituted with one or more hydroxyl groups; alkylor aryl C₁-C₁₀ esters of glycerol, pentaerythritol, ethylene glycol,propylene glycol, as well as polyethoxylated derivatives of these andpolyethylene glycol; C₁₂-C₂₂ alkyl esters or ethers of polypropylene;C₁₂-C₂₂ alkyl esters or ethers of polypropylene/polyethylene glycolcopolymer.

Non-limiting examples of occlusive emollients include cyclic and lineardimethicones; polydialkylsiloxanes; polyarylalkylsiloxanes; long chain(C₈-C₃₆)alkyl and alkenyl esters of long straight or branched chainalkyl or alkenyl alcohols or acids; long chain (C₈-C₃₆)alkyl and alkenylamides of long straight or branched chain (C₈-C₃₆)alkyl or alkenylamines or acids; hydrocarbons including straight and branched chainalkanes and alkenes such as squalene, squalane and mineral oil; jojobaoil; polysiloxane polyalkylene copolymers; short chain alkyl or arylesters (C₁-C₃₆) of C₁₂-C₂₂ diacids or diols optionally substituted withone or more hydroxyl groups such as diisopropyl dimer dilinoleate; andC₁₂-C₂₂ alkyl and alkenyl alcohols; long chain alkyl or aryl esters(C₈-C₃₆) of C₁₂-C₂₂ diacids or diols optionally substituted in availablepositions by —OH, such as diisostearyl dimer dilinoleate; lanolin andlanolin derivatives; and beeswax and its derivatives.

Non-limiting examples of humectant-type emollients include glycerol,polyglycerols (including: diglycerol, triglycerol, polyglycerin-3,tetraglycerol, hexaglycerol, decaglycerols) propylene glycol,dipropylene glycol, polypropylene glycol, polyethylene glycol (PEG-2 toPEG-45M, preferably a molecular weight between about 300 and 1,000),sorbitol, polyhydric alcohol ethoxylates (e.g., sorbeth-6, sorbeth-30,glycereth-1 to glycereth-31) methoxides of polyethylene glycol (MethoxyPEG-2 to Methoxy PEG-100) methoxides of polyhydric alcohol ethoxylates(e.g., glycereth-7 methoxide), pantothenol, gluconic acid salts and thelike. Other humectant-type agents like that could also be employedinclude: 1,2,6-hexanetriol, acetamide mea, aluminum hydroxide, argininepea, butoxypropanol, butylene glycol, dimethyl imidazolidinone,dimethylsilanol hyaluronate, dipotassium glycyrrhizate, erythritol,ethoxy-diglycol, fructose, glucamine, gluconic acid, glucose, glucoseglutamate, glucuronic acid, glutamic acid, glycogen, glycyrrhizic acid,heilmoor clay, hexacosyl glycol, histidine, hyaluronic acid,hydrogenated honey, hydrogenated starch, hydrolysate, hydrolyzedcollagen, hydrolyzed elastin, hydrolyzed glycosaminoglycans, hydrolyzedkeratin, hydrolyzed silk, hydrolyzed soy protein, hydrolyzed wheatprotein, hydroxyethyl sorbitol, inositol, inositol hexa-pea, lactamidemea, lactic acid, lactitol, lactose, lysine pea, magnesium pea,maltitol, manganese pea, mannitol, mel (honey extract), menthyl pea,methyl gluceth-10, methyl gluceth-20, pea (pidolic acid), lactamide,polydextrose, polyglucuronic acid, polyglyceryl sorbitol, potassium pea,ppg-20 methyl glucose ether, ppg-38-buteth-37, saccharide isomerate,serica, silk amino acids, sodium carboxymethyl chitin, sodium lactate,sodium mannuronate methylsilanol, sodium pea, sodium pea methylsilanol,sodium polyglutamate, soluble collagen, sorbitol, sucrose, tea-lactate,tea-pea, trehalose, trilactin, urea, xylitol, zea mays, zinc pea, andcombinations thereof.

The addition of one or more emollients may affect the viscosity andstability of the compositions of the present invention. In someembodiments, a single emollient may be added to the composition. In someembodiments, two or more emollients may be added to the composition.While any of a variety of emollients may be added to the formulations ofthe present invention, some embodiments will include wax and oil typeemollients either alone or combined with water soluble emollients. Insome embodiments of the invention, emollient systems can be comprised ofhumectants in addition to occlusive wax and oil emollients inconcentrations that achieve a moisturizing effect and which maintainsand improves the condition of the skin upon repeated use. Emollients maybe non-comedogenic and chosen to avoid skin irritation or sensitizationreactions.

H. Propellants

The formulations of the present invention are preferably notpropellant-based (i.e., substantially propellant-free orpropellant-free). However, the option of including a propellant in theinventive formulations is herein contemplated. Preferably, thepropellant is from about 3 to 45% (w/w) of the foamable formulation.More preferably, the propellant is about 5%, about 10%, about 15%, about20%, about 25%, about 30%, about 35%, about 40%, or about 45% (w/w) ofthe foamable formulation.

Without being bound by theory, the addition of propellants to inherentlyfoamable formulations (e.g., those formulations foamable by manualaeration) can provide a more consistent delivery of the active agent.For example, addition of a propellant to a foamable formulation may beuseful in producing metered dosing of the composition, as required bycertain regulatory bodies to prevent over- or under-doing. However, theaddition of a propellant is not key for deriving a foam from theformulations of the invention.

In some aspects, the formulations are capable of being formulated intoan aerosol foam or a mousse by addition of propellant to thecomposition. The propellant may form a separate layer on the compositionor the propellant may be emulsified or miscible in the composition. Theuse of emollients in a foamable composition is discussed in U.S. Pat.No. 7,651,990.

Suitable propellants can be chosen from chlorofluorocarbons (CFCs),hydrochlorofluorocarbons (HCFCs), hydrofluorocarbons (HFCs),perfluorinated alkanes, and lower alkanes (C₁-C₅) as well as nitrousoxide dimethyl ether and other solvent-soluble propellants. Suitablelower alkanes include n-pentane, propane, butane, and isobutane ormixtures thereof. In some aspects, the propellant can comprise a 70/30mixture of propane/isobutane. In other aspects, the propellant is A-46,which is a blend of 84% A-31 isobutane and 16% A 108 propane. In orderto produce an aerosol composition, the composition is first formulatedand charged into an appropriate pressure-rated container. A suitablepropellant may then be added to the composition under pressure atapproximately 1-30%, and preferably 3-20%, by volume. Non-limitingexamples of canisters useful in dispensing propellant-based foamsinclude Aptar's BOV and EP systems.

In one aspect, the composition comprises a foamable formulation aspreviously described mixed with a propellant in a ratio from about 70:30to 99:1% (w/w). In another aspect, the composition comprises a foamableformulation as previously described mixed with a propellant in a ratiofrom about 85:15 to 97:3% (w/w). In a further aspect, the compositioncomprises a foamable formulation as previously described mixed with apropellant in a ratio of about 90:10% (w/w). Preferably, the propellantis A-46.

In another embodiment, the process for preparing a propellantformulation comprises adding the propellant (e.g., at 10% concentrationby weight) to the foamable formulation (e.g., at 90% concentration byweight) and pressure-filling the cans using a Kartridge Pak pressurefiller.

I. Other Components

In one aspect, the formulation additionally comprises an anti-oxidant.Preferred anti-oxidants for use in the present invention includebutylated hydroxytoluene, butylated hydroxyanisole, ascorbyl linoleate,ascorbyl dipalmitate, ascorbyl tocopherol maleate, calcium ascorbate,carotenoids, kojic acid and its pharmaceutically acceptable salts,thioglycolic acid and its pharmaceutically acceptable salts (e.g.,ammonium), tocopherol, tocopherol acetate, tocophereth-5,tocophereth-12, tocophereth-18, or tocophereth-80.

In another aspect, the compositions of the present applicationadditionally comprise a pH-adjusting agent. In a further aspect, thepH-adjusting agent is present in an effective amount. In another aspect,the pH-adjusting agent adjusts the pH so that the active (e.g.,ibuprofen) is in a protonated form. Accordingly, the pH adjusting agentis present in an amount effective to keep the active in a protonatedform.

In one aspect, the pH-adjusting agent is a base. Suitable pH-adjustingbases include bicarbonates, carbonates, hydroxides (e.g., ammoniumhydroxide, alkali or alkaline earth metal hydroxides, transition metalhydroxides), and the like. In an alternative aspect, suitablepH-adjusting bases include amines, such as diethanolamine,triethanolamine, or aminopropanol. Additionally or alternatively, thepH-adjusting agent can be an acid, an acid salt, or mixtures thereof. Inan embodiment, the pH-adjusting agent comprises two agents (e.g., sodiumhydroxide and hydrochloric acid) that are included as needed to adjustthe final pH of the composition to a desired pH.

In an embodiment, the pH-adjusting agent is sodium carbonate. In anfurther embodiment, the composition comprises about 0.1% (w/w) to about5% (w/w), about 0.15% (w/w) to about 4% (w/w), about 0.25% (w/w) toabout 3.0% (w/w), about 0.5% (w/w) to about 2.0% (w/w) or about 1.0%(w/w) of a pH adjusting agent, suitably sodium carbonate.

Other pH-adjusting agents can also be included in the composition, suchas other acids, acid salts, or mixtures thereof. Further, thepH-adjusting agent can additionally or alternatively be a buffer.Suitable buffers include citrate/citric acid buffers, acetate/aceticacid buffers, phosphate/phosphoric acid buffers, formate/formic acidbuffers, propionate/propionic acid buffers, lactate/lactic acid buffers,carbonate/carbonic acid buffers, and the like. In one aspect, the bufferis phosphate buffered saline (PBS). In an alternate aspect, the bufferis a citrate buffer. In a further embodiment, the buffer comprises or isincluded in the water component of the hydroalcholic chassis.

In another aspect, the inventive formulation includes a buffer and asecond pH-adjusting agent (e.g., sodium hydroxide or hydrochloric acid)to adjust the pH of the composition to a desired pH. More preferably,the second pH-adjusting agent comprises two agents (e.g., sodiumhydroxide and hydrochloric acid) that are included as needed to adjustthe pH of the hydroalcoholic chassis or final composition to a desiredpH.

In still another aspect, the formulation is acidic. In certain aspects,the formulation has a pH of below about 7.5, 6.5, 5.5, 4.5, 3.5, or 2.5.In certain other aspects, the pH of the formulation may range from about1.5 to 7, about 2 to 7, about 3 to 7, about 4 to 7, or about 5 to 7. Instill other aspects, the pH of the formulation may range from about 1.5to 5.5, about 2.5 to 5.5, about 3.5 to 5.5, or about 4.5 to 5.5. Theformulation may include a buffering agent to maintain its acidic pH.Preferably, the formulation has a pH value between about 4 and 7.

In yet another aspect, the formulation is basic. In certain aspects, theformulation has a pH of above about 7, 8, 9, 10, 11, or 12. In certainother aspects, the pH of the formulation may range from about 7 to 12.5,about 7 to 11.5, about 7 to 10.5, about 7 to 9.5, or about 7 to 8.5. Instill other aspects, the pH of the formulation may range from about 9 to12.5, about 9 to 11.5, about 9 to 10.5, or about 8.5 to 10. Theformulation may include a buffering agent to maintain its basic pH.Preferably, the formulation has a pH value between about 7 and 10.

In still yet another aspect, the formulation is neutral. In certainaspects, the formulation has a pH of about 7. In certain other aspects,the formulation has a pH from about 6 to about 8.5, from about 5.5 to 8,about 6 to 8, about 6.5 to 8.5, or from about 6.5 to 7.5. Theformulation may include a buffering agent to maintain its neutral pH.Preferably, the formulation has a pH value between about 6 and 8.5.

II. Characteristics of Foamable Formulations

Foamability

Despite difficulties in foaming DMSO-based formulations, the inventorshave surprisingly been able to prepare topical DMSO formulations thatare foamable. In certain preferred aspects, the formulations of thecurrent invention have the advantage of being foamable in the absence ofa propellant. For example, the formulations are foamable by manualaeration, wherein a gas is passed through the formulation to produce afoam by manual actuation of a dispensing head. As shown in FIG. 9,DMSO-based formulations were foamed by actuating the pump head of adispensing system containing the inventive formulation.

Stability

In certain aspects of the instant invention, the foamable formulationshave the advantage of maintaining chemical or physical stability over aperiod of time. In Table 40, for instance, the chemical attributes ofpreferred formulations were monitored over the course of a three-monthperiod.

In certain aspects of the invention, the pharmaceutical composition issubstantially stable with respect to its chemical or physical attributesover a predetermined period of time. The measurable attributes mayinclude, but are not limited to, percentage of active, percentage ofimpurities, pH, or visual attributes, such as colour and the presence ofparticulates. In other aspects of the invention, the pharmaceuticalcomposition is substantially stable following storage for about 4, 8, or12 weeks at 25° C. In still other aspects of the invention, thepharmaceutical composition is substantially stable following storage forabout 4, 8, or 12 weeks at 40° C.

In previous work, long term stability results for storage of DMSO-freeibuprofen formulations demonstrated a possible interaction betweenibuprofen and ethanol that appeared to result in the production of adegradant (Compound A) presumed to be the ethyl ester of ibuprofen.Surprisingly, the foamable formulations of the present inventioncontaining ethanol show good stability after three months of storage at40° C. More surprisingly, the inventors have found that the ratio ofethanol to DMSO can be adjusted to improve foam stability. Suchcharacteristics were not previously known for DMSO-based formulations.Best foams were produced at a ratio of 0:70 to 20:60 (EtOH:DMSO)

III. Methods of Preparation

In another embodiment, the present invention provides a method formaking foamable formulations of an active agent (e.g., an NSAID, such asdiclofenac sodium or ibuprofen). The formulations of the presentinvention may be made by carrying out the following steps: (i)dispersing some or all of formulation components in dimethyl sulfoxide(preferably, the DMSO-soluble components); (ii) dissolving diclofenacsodium in an aqueous alcohol mixture (e.g., an ethanol/water mixture);(iii) dispersing propylene glycol and glycerol into the NSAID solutionfrom (ii); and (iv) mixing the resulting NSAID solution into thedimethyl sulfoxide blend. Any remaining ingredients (e.g., surfactants)can be added after preparation of the base solution. Heating can also beused during these mixing processes.

Alternatively, the formulations of the present invention may be made bycarrying out the following steps: (i) dissolving the NSAID (e.g.,diclofenac sodium) in an alcohol solution of DMSO (e.g., anethanol/dimethyl sulfoxide mixture); (ii) dispersing some or all of theformulation components in a solution of water/diol/(optionally) glycerol(preferably, the components soluble in this solution); and (iii) mixingthe NSAID solution from (i) into the thickener blend from (ii). Anyremaining ingredients (e.g., surfactants) can be added after preparationof the base solution. Heating can also be used during these mixingprocesses.

Preferably, the surfactant components can be added last to a DMSO basesolution comprising the other ingredients. See, e.g., Example 3.

The formulation can be converted to a foam by several methods. Forexample, a form can be produced by vigorously shaking or mixing theformulations (e.g., by manual shaking for 10 or 30 sec; by mixing in aVortex mixer). Preferably, the foam is produced by use of a foaming head(e.g., a dispenser such as those detailed further below; an aerosolspray dispenser).

IV. Methods of Treatment

In certain embodiments, the invention describes a method for treatingosteoarthritis comprising the step of applying a topical foamableformulation to a subject to treat the osteoarthritis.

Alternatively, the invention describes a method for treating an injurysuch as a minor strain, sprain or contusion comprising the step ofapplying a topical foamable formulation to a subject to treat theinjury.

Also included in the present application is a use of the foamableformulation of the application to treat pain as well as a topicalcomposition of the application for use to treat pain. The foamableformulations of the application are useful to alleviate acute pain,chronic pain, or both. Compositions of the application are particularlysuited for use in treating acute pain due to minor strains, sprains, andcontusions.

In aone aspect, the pain is associated with osteoarthritis. In anotheraspect, the compositions of the present application are useful for thetreatment of other chronic joint diseases characterized by joint pain,degeneration of articular cartilage, impaired movement, and stiffness.Suitable joints include, for example, the knee, elbow, hand, wrist andhip.

In another aspect, the pain is associated with inflammation. In afurther aspect, the compositions of the application are useful for thetreatment of other pain-associated disorders, including (but not limitedto) muscle pain, lower-back pain, neck pain, rheumatoid arthritis,tendonitis, fibromyalgia, myofascial pain, Carpal tunnel syndrome, goutand neuropathic pain conditions.

In certain aspects, the pharmaceutical composition is applied to a jointof the subject. Preferably, the pharmaceutical composition is applied tothe knee and the surrounding tissue.

In another aspect, the active agent (preferably, the NSAID) is deliveredlocally to the joint. In still another aspect, the active agent isdelivered to the joint with minimal systemic absorption. In yet anotheraspect, the active agent is delivered to the tissue surrounding thejoint with minimal systemic absorption.

In other aspects, the subject is a human. Alternatively, the subject isa non-human mammal.

In still other aspects, the active agent alleviates pain. Preferably,the pain is caused by arthritis or an injury. More preferably, the painis caused by osteoarthritis.

In yet still other aspects, the treatment is continued for at least 12weeks. More preferably, the treatment is continued for at least sixmonths.

In one embodiment, the treatment may be administered once a day. Inanother embodiment, the treatment may be administered twice a day. Instill another embodiment, the treatment may be administered three timesa day. In yet another embodiment, the treatment may be administered fourtimes a day. Preferably, the treatment is administered one to two timesa day.

Compositions of the present invention produce foams with measurablecharacteristics. In certain aspects, qualities such as foam stability,easiness to spread and appropriate breakability upon application to theskin or joint are desirable features. These characteristics can bemeasured by conducting foam formation and foam collapsibilityexperiments. Foam formation (foam height vs time), for example, ispredictive of the generation of a sprayable/spreadable foam. The rate ofcollapsibility is an important property in the appropriateadministration of the foam.

With reference to the figures, foam generation may be monitored bymeasuring foam height following shaking of the formulation for up to 80seconds (see FIGS. 11 to 18). Foam collapsing behavior may be monitoredby measuring foam deterioration at 0, 5 and 30 minutes following shaking(see FIGS. 19 to 22).

Compositions of the present invention may, if desired, be presented in acanister, foaming dispenser, or other closure system approved by theFood and Drug Administration (FDA) or other government regulatoryagencies, which may contain one or more unit dosage forms containing theactive ingredient. The canister or dispenser may also be accompanied bya notice associated with the container in a form prescribed by agovernmental agency regulating the manufacture, use, or sale ofpharmaceuticals, the notice indicating approval by the agency.

Formulation embodiments of the present invention are useful andeffective when applied topically to treat a condition. The amount of theactive agent present in the composition will be the amount that istherapeutically effective, i.e., an amount that will result in theeffective treatment of the condition (e.g., joint pain) when applied.The therapeutically effective amount will vary depending on the subjectand the severity of the affliction and can be determined routinely byone of ordinary skill in the art.

In another aspect, the foamable formulation comprising an active agentprovides about equal flux (as determined by the Franz cell procedure ofExample 5) as a comparative formulation containing the same activeagent.

In another, preferred aspect, the foamable formulation comprising anactive agent provides better flux than a comparative formulationcontaining the same active agent. More preferably, the flux of thefoamable formulation is at least 1.5 times the flux of the comparativeformulation's active. In other words, the ratio of (i) the formulation'sactive agent flux to (ii) the comparative formulation's active agent ispreferably greater than 1.0, and more preferably at least about 1.5.Still more preferably, the composition has a flux that is at least 2.0times greater than the flux of the comparative formulation. Yet stillmore preferably, the composition has a flux that is at least 4.0 timesgreater than the comparative formulation's flux.

In an alternative aspect, a foamable formulation comprising a diclofenacsalt has a flux about equal to the flux of a known comparativeformulation comprising the same diclofenac salt.

In another, preferred aspect, the foamable composition flux is greaterthan the flux of the comparative formulation. More preferably, thefoamable composition flux is at least 1.5 times the flux of acomparative formulation. In other words, the ratio of (i) the flux ofthe foamable composition comprising a diclofenac salt to (ii) the fluxof a comparative formulation with the same diclofenac salt is preferablygreater than 1.0, and more preferably at least about 1.5. In a preferredaspect, the comparative formulation is Pennsaid as disclosed in theExamples, wherein the formulation comprises 1.5% w/w diclofenac sodium,45.5% DMSO, water, propylene glycol, alcohol, and glycerin.

Still more preferably, the foamable composition comprising a diclofenacsalt has a flux that is at least 2.0 times the flux of a comparativeformulation having the same diclofenac salt. Yet still more preferably,the foamable composition has a flux that is at least 4.0 times the fluxof a comparative formulation.

In another alternative aspect, the present invention provides a foamablecomposition providing a diclofenac salt flux (as determined by the Franzcell procedure of Example 5) of at least 0.1 μg/hr/cm² over the first 24hours, preferably at least 0.2 μg/hr/cm² over the first 24 hours.Alternatively, the present invention provides a foamable compositionproviding an average ibuprofen flux (as determined by the Franz cellprocedure of Example 5) of at least 0.4 μg/hr/cm² over the first 24hours, and preferably, at least 0.8 μg/hr/cm² over the first 24 hours.

V. Dispensing System

Surprisingly, the compositions of the present invention may beformulated into products that can be dispensed as foams from a reservoirusing a release assembly (e.g., a hand pump) whenever the releaseassembly is put into action. The amount of the foam dispensed by thepump may or may not be metered to dispense a consistent amount of thefoam. Preferably, the amount is metered to deliver a specific dose.

Non-limiting examples of pumps useful in dispensing the compositions ofthe invention include the Rexam M3 foaming head (see, e.g., FIGS.39-41), the Rexam G3 foaming head, and the Rexam F3 foaming head. Forexamples of various Rexam pumps, see, e.g., U.S. Pat. No. 5,443,369; US2010/0320232 (WO 08/133,491); US 2009/0236371 (WO 08/007,943); U.S. Pat.No. 7,757,899 (WO 06/01445); U.S. Pat. No. 6,053,364 (WO 97/13585); US2008/0314931 (WO 07/86731); and WO 09/136,781. Other pumps useful indispensing the compositions include the Meadwestvaco Ocean T and Ocean Hspray heads. For examples of various Meadwestvaco pumps, see, e.g., US2009/0212074 (WO 06/112704); US 2009/039110 (WO 06/112701); U.S. Pat.No. 7,726,518 (WO 05/28121); U.S. Pat. No. 7,673,854 (WO 04/69418); U.S.Pat. No. 7,147,133 (WO 02/42005); U.S. Pat. No. 7,735,692 (WO 08/45822);and U.S. Pat. No. 6,547,162 (WO 99/54054). However, the compositions ofthe invention are not limited to being dispensed from only one type ofdispenser or through only one type of hand pump.

Further, the dispenser or pump head may include additional or alteredfeatures that assist in optimizing foam stability, especially forlow-viscosity formulations. These features include, but are not limitedto, the inclusion, arrangement, and hole size of meshes in the pumphead; the size and shape of the mix chamber; and varied dip tube andnozzle lengths. Non-limiting pump parameters that may assist inoptimizing foam include the output volume (e.g., 0.4 ml; 0.75 ml; 1.20ml; 1.50 ml), the stroke length (e.g., 11.0 mm; 14.8 mm; 18.8 mm). andthe thread diameter (e.g., 30; 40; 43).

Other pump parameters may be useful for ease of operation andmanufacture. Preferably, the hand pump includes only one reservoir.Preferably, the dip tube length is 18.8 mm or less.

In certain aspects, the present invention sets forth a method ofmechanically aerating a foamable DMSO formulation, thereby producing afoam. Preferably, the foam is a quick-breaking-foam. Preferably, themethod includes a step of passing the DMSO formulation and a gas througha mesh to form a foam. Preferably, the gas is air; alternatively, thegas may comprise up to 5%, 10%, or 15% (w/w) propellant.

The compositions of the invention are suitable for use on mammalian skinincluding the skin covering or surrounding a human knee joint. Innon-aerosol formulations of the invention, the compositions may becontained in a non-aerosol dispenser equipped with a conventional handpump, and the composition may be pumped onto the hands or other areas ofthe body. The pumping action required to dispense the compositions willcreate a discrete volume of a dispensed composition as a stable foam.

One method for producing a foam of the present invention comprises:providing a dispenser comprising a reservoir operably linked (e.g., influid communication) with a release assembly (e.g., dispensing head);filling the reservoir of the dispensing system with a foamableformulation as previously described; and actuating the release assemblyto manaully aerate the formulation, thereby releasing a foam from therelease assembly. This method is a particular advantage of some aspectsof the present invention, since producing a foam from a formulationcomprising DMSO by manual aeration is difficult.

EXAMPLES Example 1 Diclofenac Sodium Foaming Formulations

Materials

Diclofenac sodium was obtained from Nuvo Manufacturing (Varennes). Allingredients were USP/NF grade materials, and all excipients areavailable from commercial sources without further custom manufacturing.

TABLE 1 Chemicals CAS Chemical Name Vendor Catalog # number PlantaponACG 50 Cognis na na Pluoronic F-68 Hyclone SH30612.01 9003-11-6Pluracare L 64 BASF 52048478 na Span 80 Fluka 85548 1338-43-8 Span20Sigma S6635 1338-39-2 Tween 20 Sigma- P1379 9005-64-5 Aldrich Tween 60Acros 278620010 9005-67-8 Tween 80 Sigma- P1754 9005-65-6 AldrichPhospholipid GmbH Sample na na Brij 30 Acros 21672500 9002-92-0 Brij 58Acros 344295000 9004-95-9 Brij 78 Acros 368225000 9005-00-9 Brij 98Acros 347185000 9004-98-2 Brij 721 Spectrum B1685 9005-00-9 Polaxamer407 Spectrum P1166 9003-11-6 Sodium Laureth Stepan Steol CS-370 naSulfate (Steol CS-370) Sodium Cocoyl- Struktol n/a 61791-59-1sarcosinate (Perlastan C-30) Disodium Lauryl McIntyre n/a 26838-05-1Sulfosuccinate Glycerol Ricinoleate Phoenix na 68459-67-6 GlycerylDilaurate Pfaltz & G03120 539-93-5 Bauer Glyceryl Monooleate Pfaltz &G03225 25496-72-4 Bauer Ammonium Lauryl Spectrum A1987 68081-96-9Sulfate Triethanolamine Spectrum T1484 139-96-8 Lauryl Sulfate DocusateSodium Spectrum DO105 577-11-7 Lathanol (Sodium Stepan SPN-5779-A naLauryl Sulfoacetate) N-Lauryl Sarcosinate Sigma L5000 97-78-9 GlycerylLaurate TCI (VWR) TCG0081 142-18-7 (Glycerol Monolaurate) Sodium LaurylColonial Colonial 3088-31-1 Ether(2) Sulfate Chemicals SLES - 70%Cocamidopropyl Stepan (50%) - Amphosol CS- 68139-30-0 Hydroxysultainesample 50 Glyceryl Caprylate Abitec - Capmul MCM 26402-26-6 sample OleylBetaine McIntyre Mackam OB-30 871-37-4 groupStability of DMSO Foams I

The potential foaming qualities of excipients were tested with a DMSOsolution base. The solution base was composed of DMSO (45.5% w/w),water, propylene glycol, ethanol, glycerin, and the active agentdiclofenac sodium (1.5% w/w). In some cases, the base could be composedof Pennsaid® (DMSO and active agent as above, glycerin, water, propyleneglycol, ethanol), while in others the base contained the above amountsof DMSO and active agent, along with water (5 to 19% w/w), propyleneglycol (9 to 13% w/w), ethanol (1 to 50% such as 9.8 to 29.8% w/w) andglycerin (9.2 to 11.2% w/w) (See also US 2008/0300311 A1, incorporatedherein by reference.) Glycerin-free bases may also be used. Unless whereindicated otherwise, “DMSO base” as used herein consistutes Pennsaid®less 2% glycerine.

Each excipient was added directly to a DMSO solution base at 2% w/w. Thefoaming qualities of the formulations were then tested by two methods:

1) Vortexing: A 40-ml glass vial containing 10 ml of the formulation wasbriefly vortexed. The time for the foam to collapse was then measured.For this experiment, a foam was considered collapsed when the surface ofthe liquid was visible in the center of the vial. Residual bubbles couldstill be present around the perimeter of the glass vial.

2) Foaming Head: The formulation was dispensed from a Rexam M3 foaminghead. The dispenser was primed twice prior to dispensing on thelaboratory benchtop. The collapse time for the foam was then measured.For this experiment, a foam was considered collapsed when a distinctliquid phase was visible. A dissipating foam head still existed on topof the liquid phase, but the formulation would flow freely due to theliquid phase. This was a qualitative assessment meant to give a generalidea of foam characteristics.

The specific foam dispenser utilized in the foaming studies was acquiredfrom Airspray International, Inc, a wholly owned subsidiary of RexamInternational Groups, located at 3768 Park Central Blvd, North PompanoBeach, Fla. 33064. Specific configuration and foaming properties of theAirspray (Rexam) M3 Mini Foamer are provided in FIGS. 39-41.

Table 2 lists the results of this study. Values are in seconds.

TABLE 2 Effects of surfactant types on foam quality. Vortex foam time(in seconds unless Additive (added to DMSO Base indicated Spray at 2 wt%) pH otherwise) time Poloxamer 188 (ethylene oxide 8.82 >1 min 8, very(A)/propylene oxide (B) block liquid copolymer, A:B:A, A = 80 repeatingunits, B = 27 units) Poloxamer 407 (as 188, but A = 101, 8.76 >1 min 12,very B = 56) liquid Brij 30 (polyoxyethylene (4) lauryl 8.71 >1 min 23 ether) Brij 58 (polyoxyethylene (20) cetyl 8.7 >1 min 12  ether) Brij 78(polyoxyethylene (20) stearyl 8.7 >1 min 10  ether) Brij 98(polyoxyethylene (20) oleyl 8.4 >1 min 8 ether) Brij 721 >1 min 6Phospholipon NG90 >1 min 2, very runny Tween 20 8.48 10  2 Tween 60 8.510  2 Tween 80 8.5 18  2 Sodium lauryl sulfoacetate 7.98 4 negligibleSodium laureth sulfate 8.24 4 negligible N-lauroyl sarcosinate 6.3 3negligible Span 20 8.1 negligible negligible Span 80 8.16 negligiblenegligible Sodium cocoyl sarcosinate 8.73 negligible negligible Disodiumlauryl sulfosuccinate 7.86 negligible negligible Triethanolamine laurylsulfate 7.5 2 negligible Glyceryl dilaurate 7.98 negligible negligibleGlycerol monooleate 8.05 negligible negligible Glyceryl ricinoleate 8.36negligible negligible Glyceryl caprylate 8.6 negligible negligibleGlycerol monolaurate 8.54 3 2 Cocamidopropyl hydroxysultaine 8.5negligible negligible Oleyl betaine 8.54 negligible negligible Sodiumlauryl ether(2) sulfate 8.28 negligible negligible Amphosol 8.02 7negligible Ammonium lauryl sulfate 8.29 2 negligible Sodium docusatenegligible negligible Pluronic L-62 negligible negligible Pluronic F-6812  3 Plantapon ACG 50 negligible negligible

The majority of surfactant types produced negligible foam formation fromthe DMSO solution. Any foam produced was short-lived and dissipatedalmost immediately.

Some surfactant types formed stable foams after vortexing, but did notfoam properly upon dispensing from the foaming head. This group ofexcipients included the poloxamers and phospholipid.

Only the polyalkylene oxide alkyl ether class of surfactants (e.g.,Brij) formed a stable foam. These surfactants consistently formed themost stable foams after dispensation from the foaming head.

Example 2 Effects of Polyethylene Glycol Alkyl Ether Surfactant

A number of additives were tested in conjunction with Brij 30 inattempts to further stabilize the foam. These additives were added up to2% w/w (or up to the maximum solubility limit in the case of cetostearyland cetyl alcohol) in combination with 1% w/w Brij 30. Both the Brij 30and the additive were mixed directly with the DMSO solution.

The DMSO base was prepared as in Example 1. The space left by theremoval of the 2% glycerin was used to incorporate up to 2% w/wfoam-forming and foam-stabilizing agents.

In these studies, foam stability was estimated as the time elapsed untilthe foam completely collapsed, which is a different endpoint than when adistinct liquid phase is visible. The latter endpoint leads to a longermeasured “stability” time.

As in Example 1, the foam stability was measured both by vortexing andby dispensing from a Rexam M3 foaming head. None of the additives testedimproved the qualities of the foam made in comparison to a 2% w/w Brij30/DMSO base solution (the control).

In later experiments, foam formation studies were performed usingMeadwestvaco Ocean T and Ocean H spray heads. Experiments with longervortexing times than those performed in Table 2 were also conducted.

An outline of some of the combinations can be seen in Table 3:

TABLE 3 Polyalkylene Oxide Alkyl Ether Variants with Varying AdditivesDMSO Base Foam Formulations Base/1% Base/1% Base/ Base/ Base/ Base/ Brij30/ Brij 30/ 1% Brij 1% Brij 1% Brij 2% Brij 0.15% 0.5% 30/ 30/1%30/1.5% Base/1.5% Brij 98 Base/1% Brij 30 30 250M 250M 1% PVP PVA 407Ingredients % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w DMSO Base98.5 99 98 98.85 98.5 98 98 97.5 Brij 30 1 2 1 1 1 1 1 Brij 98 1.5Hydroxyethyl- 0.15 0.5 cellulose 250M Polyvinylpyrrolidone 1 Polyvinylalcohol 1 Poloxamer 407 1.5 Foam stability after 16 min 40 sec 9 min 20sec 5 min 10 sec 12 min 50 sec 2 min 20 sec 4 min 10 sec 6 min 20 sec 10min vortexing for 20 sec 40 sec Foam stability after 70 sec 70 sec 60-80sec 45 sec 10 sec 30 sec 30 sec 30-40 sec dispensation from a Rexam M3foaming head

Brij 30 in combination with cococaprylate, oleyl alcohol, Imwitor 948,or cholesteryl palmitate all formed foams with reduced stability incomparison to the control solution.

Cetostearyl alcohol and cetyl alcohol are relatively insoluble in thesolution base, and were added at <0.25% w/w. Both additives reduced foamstability.

Cocamide DEA was first reported as slightly increasing the stability ofthe foam. After further testing, this effect was deemed negligible. Itwas most likely observed due to difficulties in reproducibledispensations from the dispensing head.

The addition of Phospholipon NG90 with Brij 30 was observed to increasethe foam stability slightly when compared to the control. However,although the foam demonstrated some increase in stability, it wassubstantially more runny.

The addition of Poloxamer 407 with Brij 30 led to a foam withconsiderable stability when vortexed in a glass vial. This increase instability was not observed when the solution was dispensed from thefoaming head. A similar trend was also observed with sole addition ofPoloxamer 407 to the DMSO solution base (Example 1). It is possible thatPoloxamer 407 may foam sufficiently under pressurized conditions, butthat the manual foaming head dispenser is not sufficient to adequatelyform a poloxamer foam.

Thickeners were also tested in conjunction with Brij 30. Thesethickeners included hydroxylpropyl cellulose, hydroxylpropylmethylcellulose, hydroxyethyl cellulose, polyvinyl alcohol, andpolyvinylpyrrolidone. In the cases tested, increasing the viscosity ofthe formulation was detrimental to the foam quality during dispensation.

Conclusions

A DMSO foam formulation is difficult to make, with the majority ofsurfactants forming foams with less than desirable qualities. Despitethis, polyethylene glycol alkyl ethers (e.g., Brij 30, Brij 78, Brij 90,Brij 98 and the like) provided surprisingly good results. Otheradditives were tested in conjunction with Brij, but did not demonstrateany increase in foam quality/stability.

Example 3 Investigation of Foam-Stabilizing Agents

For superior properties, the foams containing polyalkylene glycol alkylether may also contain cholesterol as a foam stabilizer. Optionally,adding another ingredient such as a second surfactant may improve thefoam characteristics.

Addition of Foam Forming and Foam Stabilizing Agents: Ingredients wereincorporated into the formulation by vortexing and (if needed) byheating up to 80° C. for 10 min in a covered vial. The scale wasapproximately 20 g product per formulation batch. The formulations wereleft overnight at room temperature. The next day, the formulations werefiltered through a LuerLock NormJect syringe, Henke Sass Wolf GmbH(Tuttlingen, Germany) equipped with a 25 mm diameter Pall filter with0.2 μm GHP membrane. The product formulations were clear solutions withno suspended particles and precipitates.

TABLE 4 Selected Formulation Compositions Formulations (P100118)Ingredients I II III IV V VI VII VIII IX X XI XII DMSO base 98 98 98 9898 99.85 99.7 98 98 98 98 98 Brij 30 1.7 1.85 1.85 2 1.7 1.7 1.7 Brij 981.85 2 Cholesterol 0.15 0.15 0.15 0.3 0.15 Sodium dodecyl 0.15 0.15 0.150.15 0.15 0.15 0.15 benzene sulfonate Cetyl alcohol 0.15 Cetostearylalcohol 0.15 Oleyl alcohol 0.15

Foaming Studies: The filtered solutions were transferred into VWR 11dram glass vials with phenolic cup. The set of formulations weremanually shaken (all together) for 30 seconds. Immediately the foamheights were measured, and pictures were taken at predeterminedintervals as shown in FIGS. 1-8.

Results and Conclusions: Formulations with more lipophilic ingredients,but with some hydrophilic character provided the best foams. Obtainedfoams were repeatable, not a one-time event. Compositions VIII-X did notgive any foam. Although not pictured in this set, the foam formationproperties of XI-XII were similar to their Brij 30 counterparts.

The combination of steroids with a polyalkylene glycol alkyl ethersurfactant gave good foam stabilizing properties. A typical steroid suchas cholesterol in conjunction with Brij gave stable foams with aduration of at least 5 minutes after spraying.

To further improve the foam, a small amount of ionic surfactant (sodiumdodecylbenzene sulfate) was added into the formulations. In some cases,the addition of this surfactant further improved the formulation byforming smaller foam cells (visual observation).

At the concentrations tested, foam stabilizers such as cetyl alcohol,cetostearyl alcohol, oleyl alcohol, glycerin monolaurate, glycerinmonostearate, glycerin palmitate, glycerin monoricinoleate, and lecithin(of animal or vegetal origin) did not give stable foams when combinedwith polyethylene glycol alkyl ethers.

After 24 hours, all the foams reverted to clear solutions. Aftercollapsing of the foam, the formulation reverted to the original clearsolution, which can be re-foamed.

Example 4 Foam Spraying Studies

The formulations which appear to give stable foams in vials were sprayedusing Meadwestvaco dispensers. The formulations I and II gave spreadableand stable formulations.

At 0, 2 and 5 minute intervals, pictures were taken as shown in FIGS. 9and 10 (for 0 and 2 min).

In later studies, additional embodiments of the inventive foam wereexamined. Foam generation was monitored by measuring foam heightfollowing shaking of the formulation for up to 80 seconds (FIGS. 11 to18). Foam collapsing behavior for the P100223 series was monitored bymeasuring foam deterioration at 0, 5 and 30 minutes following shaking(see FIGS. 19 to 22; also see FIG. 25 for P100223 compositions).

Results and Conclusions

Foamable DMSO/diclofenac sodium formulations are possible. Theingredients in the formulation exhibited synergistic foaming activity.Only a convenient spraying head was needed to produce a usable foam.

Example 5 Skin Permeation Studies

General Procedure for Skin Permeation Measurement

Franz diffusion cell experiments were used to analyze flux rates ofvarying foamable formulations across a substrate membrane. Franzdiffusion cells are a common and well known method for measuringtransdermal flux rates. The general Franz cell procedure is described inFranz, T. J., Percutaneous absorption: on the relevance of in vitrodata. J. Invest. Derm., 64:190-195 (1975).

In the present Examples, Franz cells with a 3-ml receptor well volumewere used with split thickness cadaver skin (0.015″-0.018″, AlloSource)or Dermatomed porcine skin. The donor well had an area of about 0.55cm². The receptor wells were filled with isotonic phosphate-bufferedsaline (PBS) doped with 0.01% sodium azide. The receptor wells of theFranz cells were maintained at 37° C. (the temperature on the surface ofthe skin is often about 32° C.) in a stirring dry block with continualagitation via a stir bar. The flanges of the Franz cells were coatedwith vacuum grease to ensure a complete seal and were clamped togetherwith uniform pressure using a pinch clamp (SS #18 VWR 80073-350).

Porcine skin pieces were obtained from Lampire Biological Laboratories,Inc., Pipersville, Pa. Porcine skins were collected immediatelyfollowing animal sacrifice, and the hairs were trimmed with clippers.Larger pieces of excess fat were removed with a filet knife. The skinwas then trimmed to a set thickness of some 2 mm, cut into individualpieces, wrapped in aluminum foil, frozen, shipped, and stored at −78° C.Prior to use, the skin pieces were allowed to thaw, in air, to roomtemperature. Before use, the skin was dermatomed to a thickness of 0.5to 1 mm and cut into circular pieces of an appropriate size prior tomounting in the FDC.

After the Franz cells were assembled, the skin was allowed topre-hydrate for 45 minutes with PBS. The PBS was then removed and anappropriate amount of formulation was added to the skin. The dosinglevel was 3 μl per cell (˜5.5 μl/cm²). The receptor wells weremaintained at 37° C. (temperature on the surface of the skin is about30° C.) in a stirring block with continual agitation via a stir bar.Samples were drawn from the receptor wells at varying time points.Measurements were made in six-fold replicates. The concentration ofdiclofenac in the samples was then analyzed using high-performanceliquid chromatography.

Data Analysis

The cumulative amount of diclofenac transported across intact porcineskin or human cadaver skin at 4 h, 21 h, and 24 h was computed using inhouse software. In each experiment, the enhancement ratio of diclofenacdelivery from the formulations over Pennsaid® was calculated at the 24 htime point as follows:

${{Enhancement}\mspace{14mu}{Ratio}\mspace{14mu}({ER})} = \frac{\begin{matrix}{{Cumulative}\mspace{14mu}{amount}\mspace{14mu}{of}\mspace{14mu}{diclofenac}} \\{{delivered}\mspace{14mu}{from}\mspace{14mu}{test}\mspace{14mu}{formulation}}\end{matrix}}{\begin{matrix}{{Cumulative}\mspace{14mu}{amount}\mspace{14mu}{of}\mspace{14mu}{diclofenac}} \\{{delivered}\mspace{14mu}{from}\mspace{14mu}{Pennsaid}\; ®}\end{matrix}}$

Both the cumulative diclofenac delivery at the 24-hour time point andenhancement ratio is included in the tables below. A difference equal orgreater than 20% in enhancement ratio over Pennsaid® is considered ameaningful difference. If the difference between the test formulationand the Pennsaid® control is within 20%, it is concluded that thediclofenac delivery from the test formulation has no demonstratedadvantage over Pennsaid®.

Results

As illustrated in FIGS. 23 to 26, the inventive formulations (P100223,P100118, P100201) performed equally or better than the comparator(Pennsaid®).

Foaming Studies

The inventive formulations were additionally tested for foam stability.Results of the foam stabilization study (Table 5 below) from variouscombinations of surfactants and steroids showed that the combination ofBrij and cholesterol (P100118-02) produced similar foam stability as thecombination of Brij, cholesterol and SDBS (P100118-01). See FIGS. 23-26.Both P100118-01 and P100118-02 produced stable foams with the greatestfoam heights suggesting that combinations of Brij 30, cholesterol andSDBS can produce stable foams. Furthermore, it appears that cholesterolis an effective foam stabilizer. Brij-containing formulations withoutcholesterol (P100118-03 and P100118-05) showed a rapid reduction in foamheights when compared to Brij-containing formulations with cholesterol.The lowest foam height was observed with formulation P100118-04, whichdoes not contain Brij. Comparison of the foam heights betweenformulations P100118-01 and P100118-04, P100118-06, and P100118-07strongly suggests that Brij is essential for foam formation from theDMSO base formulation.

TABLE 5 Foam Stability of Foamable DMSO Base Solutions containingVarious Combinations of Surfactants and Steroids Foam Heights (mm) atDifferent Time point Formulation 0 min 2 mins 5 mins 30 mins 60 mins 120mins 180 mins P100118-01 108.2 95.2 86.0 73.0 66.3 63.7 58.2 P100118-02107.7 95.5 86.2 69.3 64.8 58.2 55.2 P100118-03 62.3 42.5 13.7 0.0 0.00.0 0.0 P100118-04 5.3 5.8 3.7 4.2 2.7 1.5 0.0 P100118-05 58.7 33.0 8.20.0 0.0 0.0 0.0 P100118-06 0.0 0.0 0.0 0.0 0.0 0.0 0.0 P100118-07 0.00.0 0.0 0.0 0.0 0.0 0.0 P100118-08* 0.0 0.0 0.0 0.0 0.0 0.0 0.0 *BaseSolution

Example 6 Foam Stabilization and Permeation Studies, P100310 Series

A second set of formulations includes combinations of Brij 30, Brij 78,cholesterol, and sodium laureth sulfate (SLES); formulation compositionsof these formulations are presented in Table 6 below.

TABLE 6 Formulation Composition of Foamable DMSO Base SolutionsContaining Brij 30 and 78, Cholesterol, and SLES Formulations (w/w %)P100310- P100310- P100310- P100310- P100310- P100310- P100310- P100310-P100310- Ingredients 01 02 03 04 05 06 07 08 09 DMSO Base 98 98.05 98.198.05 98.1 98.15 98.1 98.15 98.2 Brij 30 1 1 1 1 1 1 1 1 1 Cholesterol0.15 0.1 0.05 0.15 0.1 0.05 0.15 0.1 0.05 SLES 0.15 0.15 0.15 0.1 0.10.1 0.05 0.05 0.05 Brij 78 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7 0.7

Foams were produced with a Rexam M3 foaming dispenser after the foamhead was primed four times, after which the foam was dispensed to backof a volunteer's hand. The foam was considered to have collapsed whenliquid started to appear at the base of the foam (leak). The followingscale was used to measure collapse of foams:

-   -   3=No leak; 2=slight leak; 1=leak        Results are presented in Table 7 and FIG. 27.

It appears that formulations P100310-01, P100310-02, P100310-03,P100310-07 and P100310-08 produced stable foams when dispensed from theRexam M3 foaming dispenser. P100310-01 produced the most stable foamthat did not collapse after 2 minutes. The ranking order of foamstability isP100310-01>P100310-02=P100310-03=P100310-08>P100310-04=P100310-05=P100310-06=P100310-07=P100310-09.

TABLE 7 Foam Stability of P 100310 Series of Formulations over Twominutes Following Dispensing with Rexam M3 Foamer on the Hand of aVolunteer Foam Quality Scale Time P100310- P100310- P100310- P100310-P100310- P100310- P100310- P100310- P100310- (min) 01 02 03 04 05 06 0708 09 0 hr 3 3 3 3 3 3 3 3 3 1 min 3 3 3 2 3 2 3 3 1 2 min 3 2 2 1 1 1 12 1

In a second assessment, foam was dispensed to the back of a volunteer'shand from the Rexam M3 dispenser and was gently spread with one stroke.The following scale was used to measure collapse of the foam afterspreading:

-   5=hard foam; 4=light foam; 3=very light foam; 2=slightly light foam;    1=no foam

The formulations P100310-03 and P100310-06 were completely collapsedafter 2 minutes. The ranking order of foam stability wasP100310-01>P100310-02=P100310-06>P100310-04>P100310-07=P10310-08>P100310-03=P100310-06.Results are presented in Table 8 and FIG. 28. Pictures of the foams areincluded in FIGS. 42 through 50.

TABLE 8 Foam Stability of P100310 Series of Formulation over Two MinutesAfter Spreading Foam quality of formulations Time P100310- P100310-P100310- P100310- P100310- P100310- P100310- P100310- P100310- (min) 0102 03 04 05 06 07 08 09 0 hr 5 5 5 4 5 4 5 4 4 1 min 5 5 4 4 5 1 4 4 3 2min 5 4 1 3 4 1 3 3 2Conclusions on Foam Stabilization Studies

Thickeners including hydroxyethyl cellulose, polyvinylpyrrolidone,polyvinyl alcohol, poloxamer 407, cetostearyl alcohol, cetyl alcohol,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, oleyl alcohol,glycerine monoricinoleate, glycerine monolaurate, glycerine monosterate,glycerine palmitate and lecithin did not stabilize foams produced fromthe DMSO base formulation containing non-ionic surfactant Brij 30.Stable foams with a collapse time greater than 2 minutes were obtainedfrom DMSO base formulation that contains a combination of non-ionicsurfactants (Brij 30 and Brij 78), a steroid (cholesterol) and ananionic surfactant (SLES or SDBS) when dispensed from the Rexam M3foaming dispenser. Both SDBS and SLES are listed on the FDA InactiveIngredient List (IIG) for topical use; however, SDBS is listed for usein wash off products and SLES is listed for washed off and non-washedoff products. Since Pennsaid® is indicated for non-wash off use, SLESwas considered as the preferred anionic surfactant for furtherevaluation.

Based on the stability of the foam dispensed from the Rexam M3 foamingdispenser and the ease of collapsing the foam upon spreading, fourfoamable formulations with the combination of non-ionic surfactants(Brij 30 and Brij 78), a steroid (cholesterol) and an anionic surfactant(SLES) were identified, i.e., P100310-01, P100310-03, P100310-07 andP100310-08. Each of these four formulations contains the sameconcentration of Brij 30 and Brij 78, but different concentrations ofcholesterol and SLES. Formulation P100310-01 is considered too stablesince it did not collapse easily after spreading on the skin.Formulations P100310-03, P100310-07, and P100310-08 have similar foamstability characteristics when dispensed onto the skin. However,formulation P100310-03 collapses much more readily than P100310-07 andP100310-08 after the formulation is spread across the application site.

In vitro Permeation Studies

The in vitro diclofenac delivery results for the P100310 seriesformulations are presented in Table 9 and in FIG. 29. A modified versionof the procedure set out in Example 5 was used. Based on the enhancementration results, all P100310 series formulations showed equivalentdiclofenac delivery relative to Pennsaid®.

TABLE 9 In Vitro Diclofenac Delivery from P100310 Series FoamableFormulations Cumulative Amount of Diclofenac (μg/cm²; avg ± sem)P100310- P100310- P100310- P100310- P100310- P100310- P100310- P100310-P100310- Time 01 02 03 04 05 06 07 08 09 Pennsaid ®  4  0.83 ± 0.36 0.65 ± 0.40  0.73 ± 0.33  1.11 ± 0.73  1.26 ± 1.04  2.53 ± 1.03  1.09 ±0.50  0.40 ± 0.22 0.32 ± 0.32  3.12 ± 1.43 hrs 21 14.36 ± 1.54 16.00 ±2.58 16.98 ± 2.16 13.95 ± 3.10 12.09 ± 0.59 12.42 ± 1.80 12.66 ± 0.28 9.49 ± 1.09 8.38 ± 2.35 14.30 ± 6.89 hrs 24 12.49 ± 0.90 12.32 ± 1.4414.34 ± 1.33 13.22 ± 2.63 13.17 ± 0.48 12.63 ± 1.73 13.50 ± 0.83 10.49 ±0.88 8.59 ± 1.84 12.18 ± 5.39 hrs ER 1.03 1.01 1.18 1.09 1.08 1.04 1.110.86 0.79 1.00

In summary, both P100223 (FIGS. 19-22, 24-25) and P100310 seriesformulations delivered equivalent amount of diclofenac as Pennsaid®.However, the foam characterization studies showed that P100310 seriesfoamable formulations generated stable foams that are easy to spread.

Example 7 Formulation Studies of P100310-01

A further formulation optimization study was carried out with P100310-01to determine the optimal concentrations of Brij 30, Brij 78,cholesterol, and SLES.

Formulation P100310-01 was coded as the P100323 series. The design ofthe formulation composition is presented in Table 10. Preliminary foamquality studies were conducted using the vortex mixing method anddiclofenac delivery studies performed using with Franz diffusion cellsystem as described in Example 5.

TABLE 10 Formulation Compositions of the P100323 Series FormulationsIngredients P100323- P100323- P100323- P100323- P100323- P100323- (w/w%) 01^(a) 02 03 04 05 06 DMSO Base 98 99 98.15 98.15 98.7 98 Brij 30 1 01 1 1 0.7 Cholesterol 0.15 0.15 0 0.15 0.15 0.15 Sodium laureth 0.150.15 0.15 0 0.15 0.15 sulfate Brij 78 0.7 0.7 0.7 0.7 0 1 ^(a)=P100310-01Foam Stability and Diclofenac Delivery of the P100323 SeriesFormulations

Results (FIG. 30) from the preliminary foaming studies indicate thatP100323-03 produced the least stable foam, suggesting that cholesterolimproves foam stability. All other formulations showed similar foamstability. Varying the Brij 30 concentration from 1.0 w/w % to 0.7 w/w%, Brij 78 concentration from 0 w/w % to 0.7 w/w % and 1.0 w/w %, andSLES concentration from 0 w/w % to 0.15 w/w % did not impact foamstability when assessed by the vortex mixing method.

The results for the Franz diffusion cell delivery studies are presentedin FIG. 31 and Table 11 below. Based on the enhancement ratios, allformulations with the exception of P100323-03 showed equivalentdiclofenac delivery relative to Pennsaid®. Pictures for foam stabilityare presented in FIGS. 42 to 50.

TABLE 11 In Vitro Diclofenac Delivery across Intact Human Cadaver Skinfrom P100323 Series Formulations Formulations/Cumulative Amount ofDiclofenac (μg/cm²; avg ± sem) P100323- P100323- P100323- P100323-P100323- P100323- Time 01 02 03 04 05 06 Pennsaid ®  4 hrs 11.57 ± 2.9715.08 ± 3.16 17.86 ± 1.07  5.96 ± 1.65  8.58 ± 1.52 13.17 ± 1.68 12.90 ±2.47 21 hrs 29.67 ± 3.10 33.30 ± 2.81 41.08 ± 2.53 27.20 ± 2.88 33.37 ±2.34 32.08 ± 1.72 30.76 ± 1.94 24 hrs 28.21 ± 2.97 33.23 ± 2.26 39.58 ±2.08 28.09 ± 2.47 30.93 ± 1.91 30.52 ± 2.92 30.42 ± 2.06 ER 0.93 1.091.30 0.92 1.02 1.00 1.00Conclusions from the P100323 Series Study

The absence of cholesterol in these formulations resulted in poor foamstability. Varying the concentrations of Brij 30, Brij 78 and SLES didnot change foam stability characteristics. However, assessment of foamcharacteristics by the Rexam M3 foaming dispenser, a more relevantassessment, was not conducted except for formulation P100323-01 whichshowed good foam stability. All formulations with the exception ofP100323-03 (no cholesterol) showed comparable diclofenac delivery toPennsaid®. Formulation P100323-01 (P100310-01) delivered diclofenacacross intact human skin equivalent to Pennsaid®, and it formed a stablefoam when dispensed from the Rexam M3 foaming dispenser.

Example 8 Formulation Studies of P100310-03, P100312 Series

A further formulation optimization study were carried out withP100310-03 to determine the optimal concentrations of Brij 30, Brij 78,cholesterol, and SLES.

Formulation P100310-03 was coded as the P100312 series. Formulationcompositions are presented in Table 12. Preliminary foam quality studieswere conducted using both the vortex mixing method and from a Rexam M3foaming dispenser. Diclofenac delivery from these formulations was alsoassessed using Franz diffusion cells as described in Example 5.

TABLE 12 Formulation Compositions of the P100312 Series FormulationsIngredients P100312- P100312- P100312- P100312- P100312- P100312- (w/w%) 01^(a) 02 03 04 05 06 DMSO Base 98.1 99.1 98.15 98.25 98.8 98.1 Brij30 1 0 1 1 1 0.7 Cholesterol 0.05 0.05 0 0.05 0.05 0.05 Sodium laureth0.15 0.15 0.15 0 0.15 0.15 sulfate Brij 78 0.7 0.7 0.7 0.7 0 1 ^(a)=P100310-03Foam Stability and Diclofenac Delivery of the P100312 Series

Results (FIG. 32) from the preliminary foaming studies using the vortexmixing method indicate that P100312-03 gave the least stable foam,suggesting that cholesterol improves foam stability. All otherformulations showed similar foam stability. Varying Brij 30concentration from 1.0 w/w % to 0.7 w/w %, Brij 78 concentration from 0w/w % to 0.7 w/w % and 1.0 w/w, and SLES concentration from 0 w/w % to0.15 w/w % did not have any impact on foam stability. Results from thefoam stability study using the Rexam M3 foaming dispenser showed thatP100312-01 yield the best foaming characteristics.

Pictures for foam stability tests are presented in FIGS. 51 to 55.

Results from the Franz diffusion cell studies are presented in FIG. 33and Table 13. With the exception of P100312006, all other formulationsin the series showed equivalent diclofenac delivery relative toPennsaid®.

TABLE 13 Diclofenac Sodium Permeation of the P100312 SeriesFormulations/Cumulative Amount of Diclofenac (μs/cm²; avg ± sem)P100312- P100312- P100312- P100312- P100312- DMSO Time 01 03 04 05 06Base  4 hrs  2.21 ± 1.34  2.24 ± 0.74  2.67 ± 1.43  1.43 ± 0.39  2.02 ±1.20  5.46 ± 1.72 21 hrs 18.90 ± 4.30 20.33 ± 3.17 18.76 ± 5.48 18.47 ±1.95 16.79 ± 2.79 24.45 ± 3.44 24 hrs 19.99 ± 3.88 22.03 ± 3.40 20.01 ±6.02 20.51 ± 2.06 17.95 ± 2.82 24.14 ± 3.78 ER 0.83 0.91 0.83 0.85 0.741.00Conclusions from Studies of the P100312 Series Study

In these formulations, the absence of cholesterol results in poor foamstability. Varying the concentrations of Brij 30, Brij 78 and SLES didnot change foam stability characteristics. Assessment of foamcharacteristics by the Rexam M3 foaming dispenser showed that P100312-01has the best foam stability. All formulations with the exception ofP100312-03 (no cholesterol) showed comparable diclofenac delivery toPennsaid®. Formulation P100312-01 (P100310-03) has equivalent diclofenacdelivery to Pennsaid®, and it formed a stable foam when dispensed fromthe Rexam M3 foaming dispenser.

Example 9 Formulation Studies of P100310-07, P100325 Series

A further formulation optimization study were carried out withP100310-07 to determine the optimal concentrations of Brij 30, Brij 78,cholesterol, and SLES.

Formulation P100310-07 was coded as the P100325 series. The formulationcompositions are presented in Table 14. Preliminary foam quality studieswere conducted using the vortex mixing method, and diclofenac deliverywas assessed using Franz diffusion cells as described in Example 5.

TABLE 14 Formulation Compositions of the P100325 Series FormulationsIngredients P100325- P100325- P100325- P100325- P100325- P100325- (w/w%) 01^(a) 02 03 04 05 06 DMSO Base 98.1 99.1 98.25 98.15 98.8 98.1 Brij30 1 0 1 1 1 0.7 Cholesterol 0.15 0.15 0 0.15 0.15 0.15 Sodium laureth0.05 0.05 0.05 0 0.05 0.05 sulfate Brij 78 0.7 0.7 0.7 0.7 0 1 ^(a)=P100310-07Foam Stability and Diclofenac Delivery of the P100325 Series

Results from the preliminary foaming studies (FIG. 34) indicate thatP100325-03 produced the least stable foam, suggesting that cholesterolimproves foam stability. All other formulations showed similar foamstability. Varying Brij 30 concentration from 1.0 w/w % to 0.7 w/w %,Brij 78 concentration from 0 w/w % to 0.7 w/w % and 1.0 w/w %, and SLESconcentration from 0 w/w % to 0.05 w/w % did not have any impact on foamstability when assessed by the vortex mixing method.

The results for the Franz diffusion cell permeation studies arepresented in FIG. 35 and Table 15. Formulations P100325-01 andP100325-02 showed equivalent diclofenac delivery relative to thePennsaid® control. Formulations P100325-03, P100325-04, P100325-05 andP100325-06 showed higher diclofenac delivery than the Pennsaid® control.

TABLE 15 Diclofenac Sodium Permeation of the P100325 SeriesFormulations/Cumulative Amount of Diclofenac (μg/cm²; avg ± sem)P100325- P100325- P100325- P100325- P100325- P100325- Time 01 02 03 0405 06 Pennsaid ®  4 hrs 0.00 ± 0.00 0.00 ± 0.00  0.42 ± 0.42  0.48 ±0.31  1.34 ± 0.57  0.20 ± 0.20 0.39 ± 0.27 21 hrs 6.54 ± 1.17 5.59 ±0.99 12.57 ± 1.90 11.30 ± 2.05 13.12 ± 1.98 10.00 ± 1.23 5.31 ± 1.90 24hrs 8.35 ± 1.27 7.67 ± 1.22 15.72 ± 2.22 14.62 ± 2.79 16.34 ± 2.81 13.89± 1.68 7.65 ± 2.45 ER 1.09 1.00 2.05 1.92 2.14 1.82 1.00Conclusions from the P100325 Series Study

In these formulations, the absence of cholesterol results in poor foamstability. Varying the concentrations of Brij 30, Brij 78 and SLES didnot change foam stability characteristics. However, assessment of foamcharacteristics by the Rexam M3 foaming dispenser was not performedexcept for formulation P100325-01 which demonstrated good foamstability. Formulations P100325-01 and P100325-02 showed equivalentdiclofenac delivery relative to Pennsaid®; all other formulations showedhigher diclofenac sodium delivery than Pennsaid®. Formulation P100325-01(P100310-07) has equivalent diclofenac delivery relative to Pennsaid®,and it formed a stable foam when dispensed from the Rexam M3 foamingdispenser.

Example 10 Formulation Optimization Studies of P100310-08, P100324Series

A further formulation optimization study were carried out withP100310-08 to determine the optimal concentrations of Brij 30, Brij 78,cholesterol, and SLES.

The formulation P100310-08 was coded as the P100324 series. Theformulation composition is presented in Table 16. Preliminary foamquality studies were conducted using the vortex mixing method, anddiclofenac delivery was assessed using Franz diffusion cells wasassessed.

TABLE 16 Formulation Composition for the P100324 Series FormulationsIngredients P100324- P100324- P100324- P100324- P100324- P100324- (w/w%) 01^(a) 02 03 04 05 06 DMSO Base 98.15 99.15 98.25 98.2 98.85 98.15Brij 30 1 0 1 1 1 0.7 Cholesterol 0.1 0.1 0 0.1 0.1 0.1 Sodium laureth0.05 0.05 0.05 0 0.05 0.05 sulfate Brij 78 0.7 0.7 0.7 0.7 0 1Foam Stability and Diclofenac Delivery for the P100324 Series

Results (FIG. 36) from the preliminary foaming studies indicate thatP100324-03 produced the least stable foam, suggesting that cholesterolimproves foam stability. All other formulations showed similar foamstability. Varying Brij 30 concentrations from 1.0 w/w % to 0.7 w/w %,Brij 78 from 0 w/w % to 0.7 w/w % and 1.0 w/w %, SLES from 0 w/w % to0.05 w/w %, did not have any impact on foam stability when assessed bythe vortex method.

Results from the Franz diffusion cell studies are presented in FIG. 37and Table 17. All formulations with the exception of P100324-05 andP100324-06 showed equivalent diclofenac delivery relative to Pennsaid®.Formulations P100324-05 and P100324-06 showed higher diclofenac deliveryas compared to Pennsaid®.

TABLE 17 Diclofenac Delivery for the P100324 Series FormulationsCumulative Amount of Diclofenac (μg/cm²; avg ± sem) P100324- P100324-P100324- P100324- P100324- Time P100324-01^(a) 02 03 04 05 06 Pennsaid ® 4 hrs  2.87 ± 0.74  1.60 ± 0.90  2.94 ± 0.93  2.09 ± 0.81  3.20 ± 0.93 2.40 ± 0.53  1.63 ± 0.89 21 hrs 25.42 ± 3.09 23.15 ± 4.68 32.38 ± 4.0517.85 ± 2.43 37.17 ± 2.30 31.94 ± 4.15 21.84 ± 1.52 24 hrs 24.33 ± 3.1924.16 ± 4.08 31.12 ± 3.12 20.05 ± 2.96 38.94 ± 3.20 35.11 ± 4.26 25.89 ±1.63 ER 0.94 0.93 1.20 0.77 1.50 1.36 1.00 ^(a)= P100310-08Conclusions from the P100324 Series Study

In these formulations, the absence of cholesterol results in poor foamstability. Varying the concentrations of Brij 30, Brij 78 and SLES didnot change foam stability characteristics. However, assessment of foamcharacteristics by the Rexam M3 foaming dispenser was not conducted,except for formulation P100324-01, which showed good foam stability. Allformulations except for P100324-05 and P100324-06 showed equivalentdiclofenac accumulation relative to Pennsaid®. Formulation P100324-01(P100310-08) delivered equivalent amount of diclofenac relative toPennsaid®, and it formed stable foam when dispensed from the Rexam M3foaming dispenser.

Example 11 General Laboratory Batch Manufacturing Process

The following small-scale, 100-g laboratory batch manufacturing processwas established.

Diclofenac sodium, Brij 30, Brij 78, SLES, ethanol, and water are addedto a suitable container and mixed until dissolved. DMSO, propyleneglycol, glycerine, and cholesterol are added to a second suitablecontainer and mixed until homogeneous. The diclofenac/Brij solution isadded to the second container and mixed until homogenous. The combinedmixture is stirred overnight at room temperature. The mixture is thenfiltered through a 0.2 micrometer pore-size filter and added intosuitable containers.

Example 12 Comparison of Four Selected P100310 Formulations

Diclofenac Delivery

The diclofenac deliveries from the P100310 formulations were assessedusing Franz diffusion cell and human cadaver skin. Pennsaid® wasincluded as a control in this study. Compositions of the P100310formulations are presented in the table below.

TABLE 18 Composition of Selected P100310 Formulations % w/w compositionP100310-01 P100310-03 P100310-07 P100310-08 or or or or ExcipientP100323-01 P100312-01 P100325-01 P100324-01 DMSO Base 98.00 98.10 98.1098.15 Brij 30 1.00 1.00 1.00 1.00 Brij 78 0.7 0.7 0.7 0.7 Cholesterol0.15 0.05 0.15 0.10 SLES 0.15 0.15 0.05 0.05

The results for the Franz diffusion cell study are presented in FIG. 38and Table 19. The diclofenac delivery was similar among the fourformulations; all four formulations showed equivalent diclofenacdelivery relative to Pennsaid®.

TABLE 19 Comparative Diclofenac Delivery from the Selected P100310Formulations Cumulative Amount of Diclofenac (μg/cm^(2;) avg ± sem) TimeP100310-01 P100310-03 P100310-07 P100310-08 Pennsaid ®  4 hrs  7.68 ±2.45  7.68 ± 4.30  4.98 ± 2.04  7.66 ± 3.30 10.63 ± 6.39 21 hrs 35.22 ±4.14 35.97 ± 6.41 32.55 ± 2.54 41.45 ± 4.47 36.81 ± 7.33 24 hrs 37.80 ±3.48 41.17 ± 6.88 30.78 ± 2.10 39.59 ± 3.81 34.36 ± 6.77 ER 1.10 1.200.90 1.15 1.00Physicochemical Parameters of Selected P100310 Formulations

The physicochemical properties, pH and specific gravity of the fourformulations were measured and compared to Pennsaid® and are presentedin the table below. Further measurements of specific gravity may becarried out using a calibrated picnometer using techniques generallyknown in the art. Both pH and specific gravity for each of the fourformulations selected are comparable to each other, and are within thespecifications described for Pennsaid®.

TABLE 20 Physicochemical Properties of P100310 Formulations SpecificGravity^(b) Formulation pH^(a) ± SD (g/mL) ± SD P100310-01 8.38 ± 0.031.045 ± 2.01 P100310-03 8.42 ± 0.07 1.046 ± 2.41 P100310-07 8.48 ± 0.061.043 ± 1.3  P100310-08 8.52 ± 0.08 1.040 ± 0.54 Pennsaid ® 8.0-9.51.030-1.110 ^(a)pH was measured with a Fisher AR 15 pH meter; ^(b)wasdetermined with 5 mL volumetric flaskConclusions

The development of a foamable DMSO formulation has been accomplished by(i) combining a DMSO base solution with suitable surfactants and a foamstabilizer, and (ii) dispensing from a suitable foam-dispensing pump. Inthis study, stable foams with a collapse time greater than two minuteswhen dispensed from a Rexam M3 foaming dispenser were obtained from thecombination of Brij 30, Brij 78, cholesterol and SLES.

Four formulations of interest were identified: P100310-01, P100310-03,P100310-07 and P100310-08. These formulations have the sameconcentration of Brij 30 (1.0 w/w %) and Brij 78 (0.7 w/w %) butdifferent concentrations of cholesterol or SLES. The four formulationsdisplayed equivalent diclofenac delivery relative to Pennsaid®, but withdifferent foaming characteristics. Formulation P100310-01 was verystable and did not collapse quickly after application. FormulationsP100310-03, P100310-07, and P100310-8 have similar foam stabilitycharacteristics following dispensing onto the skin surface. However,formulation P100310-03 collapses much more readily than P100310-07 andP100310-08 after the formulation is spread across the application site.

Formulation P100310-03 has several desirable properties, including:

-   -   producing a foam after dispension from a suitable foaming device        so that (i) before contacting the skin; the foam is stable for        ≧2 mins before it starts to disintegrate (i.e., collapse); (ii)        the foam should be spreadable; and (iii) the foam collapsed        quickly when gently rubbed into the skin; and    -   providing a diclofenac delivery equivalent to or better than the        control Pennsaid®.

Example 13 General Procedures for Testing of Sprayable, MicrostructuredIbuprofen Formulation

A sprayable, microstructured ibuprofen formulation suitable for twice aday (b.i.d) dosing that achieves ≧two times the 12 hour accumulated fluxof the comparator gel was investigated. The comparator gel IBUGEL®(ibuprofen 5% w/w gel) is a topical product marketed in the UnitedKingdom, Ireland and Luxembourg for the treatment of acute painassociated with soft-tissue injuries, sprains and strains.

Long-term storage stability of DMSO-free ibuprofen gel formulationsdemonstrated a possible interaction between ibuprofen and ethanolresulting in the production of Compound A, a degradant presumed to theethyl ester of ibuprofen. The foam-type formulation was designed to havean improved stability profile while providing at least two-fold higherpermeation of ibuprofen as compared to Ibugel.

Materials

Ibuprofen, USP is the active pharmaceutical ingredient (API) in theseformulations. The API used for the experiments described in thisapplication was sourced from Albemarle, USA and met the compendialrequirements of USP. Ibuprofen [i.e., 2-(4-isobutylphenyl) propanoicacid] is a member of the propionic acid group of non-steroidalanti-inflammatory compounds. The ibuprofen used for the followingstudies was a racemic mixture.

Ibuprofen is a white to off-white powder, practically insoluble in water(<0.1 mg/ml), but readily soluble in organic solvents such as ethanoland acetone. The compound has a melting point range of 75 to 77° C., apKa value of 4.91 and a log P value of 3.6 (DrugBank: a comprehensiveresource for in silico drug discovery and exploration. Wishart D S, KnoxC, Guo A C, Shrivastava S, Hassanali M, Stothard P, Chang Z, Woolsey J.Nucleic Acids Res. 2006 Jan. 1; 34 (Database issue):D668-72. PMID:16381955).

Table 21 provides a list of the materials used for the formulationscreening activities described in this report and the sourcinginformation for the materials.

TABLE 21 Materials used in Formulation Screening Experiments forIbuprofen (5% w/w) Foam Formulations CAS Chemical name AbbreviationNumber Source Ibuprofen — 15687-27-1 Albemarle Dimethyl sulfoxide DMSO67-68-5 Sigma Aldrich Ethanol — 64-17-5 Sigma-Aldrich Water — — —Propylene glycol PG 57-55-6 Unilever Glycerin — 56-81-5 J T BakerPolyoxyl stearyl ether Brij 78 9005-00-9 Acros Polyoxyl lauryl etherBrij 30 9002-92-0 Spectrum Sodium lauryl sulfate SLS 151-21-5 SigmaAldrich Sodium laureth sulfate SLES NR Stepan (Not Recorded) Sodiumcarbonate 497-19-8 Spectrum Cocoamidopropyl Amphosol 61789-40-0 Stepanbetaine (Amphosol ® HCG) Diethylene glycol Transcutol 111-90-0 FlukaChemicals monoethyl ether (Transcutol ®) Disodium DCAM 68650-39-5 Rhodiacocoamphodiacetate Lactic Acid — 50-21-5 Sigma Aldrich Triethyl citrateTEC 77-93-0 Spectrum, Sigma Aldrich, SAFC Methyl paraben — 99-76-3Spectrum Propyl paraben — 94-13-3 Sigma Aldrich Cholesterol 57-88-5Sigma Aldrich, J T Baker Phosphate buffered saline PBS — — Hydroxypropylcellulose HPC 9004-64-2 Spectrum, (HY 121, HY 117) HerculesPoly(ethylene oxide-co- Poloxamer 9003-11-6 Spectrum Polypropyleneoxide) 407 Polyvinyl alcohol PVA 9002-89-5 Sigma Aldrich Human cadaverskin — — Allosource (Centennial, CO, USA) Porcine skin — — LampireBiological Laboratories (Pipersville, PA, USA)Equipment

High-performance liquid chromatography (HPLC) was conducted with anAgilent 1200 HPLC analytical system equipped with UV detector (ModelG1313D DAD; Agilent Technologies, Waldbronn, Germany). The dermatomeprocedures were conducted with a Zimmer® electric dermatome (ZimmerOrthopaedic Products, Dover, Ohio 44622, USA) The other equipment usedin the following procedures includes a Nichiryo 8100 Applicator(Nichiryo, Tokyo, Japan), Franz diffusion cells (FDC) 3 mL volume(Chemglass, Vineland, N.J., USA), anincubator (VWR Scientific Model1565), and aHarris Classic Freezer (Model HLT-17V-85D14; HarrisManufacturing Co., Asheville, N.C., USA).

Skin Storage and Dermatome Procedure

Excised Yorkshire pig (Sus domestica) skin was provided by LampireBiological Laboratories (Pipersville, Pa., USA). Human cadaver skin wasprovided by Allosource (Centennial, Colo., USA). Upon receipt, skinsamples were frozen immediately and stored at Ca −80° C. until needed.Prior to use, skin was removed from the freezer and thawed at roomtemperature (ca. 45 minutes). Following thawing, skin pieces weredermatomed to a thickness of 0.8 to 1.0 mm using the procedure describedin Example 5.

Franz Cell Set-up for In Vitro Permeability Studies

In vitro permeability studies were conducted using Franz diffusion cells(FDCs) as outlined in Example 5. Dermatomed porcine skin was used as theskin substrate. Human cadaver skin was used in the definitive fluxexperiments. The general procedure for these permeation experiments isdescribed below.

Franz diffusion cells with a 3.3 ml receiver volume and 0.55 cm² crosssectional area were used. Receptor wells were filled with phosphatebuffered saline (PBS) containing 0.01% sodium azide (used as apreservative). Sections of skin (˜2×2 cm) were mounted on the receptorcells. The flanges of the FDCs were coated with vacuum grease to ensurea complete seal and clamped together with uniform pressure using a pinchclamp. Any excess skin was trimmed with a pair of stainless-steelscissors. After assembly of the FDCs, the skin was allowed to rehydratefor ca. 20 minutes. The test formulations were applied, and the FDCset-up was placed in an incubator at 32° C. The receptor fluid wascontinuously stirred and maintained at 32±0.5° C. throughout theexperiments. Measurements for each formulation were carried out in 6-8fold replicates.

Formulation Application and Analysis

Typically, 3 μl of the formulation was applied to the donor chamberusing the Nichiryo sample applicator. The commercial formulation Ibugel(ibuprofen 5% w/w gel) was used as comparator and was also applied as a3 μl dose to the skin surface in the donor chamber.

300 μL sample aliquots were drawn from the receptor sampling ports witha Hamilton-type injector. The sample volume was replaced with fresh PBScontaining 0.01% sodium azide. Aliquots were typically withdrawn at 4,21 and 24 hours after sample application, unless specifically indicated.

Aliquots of receptor fluid were analyzed by HPLC.

Data Analysis

The cumulative amounts of ibuprofen transported across porcine skin at 4h, 21 h, and 24 h were computed. In each case, the enhancement inibuprofen delivery from the test formulations over the control Ibugelformulation was calculated at the 24 h time point as follows:

${{Enhancement}\mspace{14mu}{ratio}\mspace{14mu}({ER})} = \frac{\begin{matrix}{{Mean}\mspace{14mu}{cumulative}\mspace{14mu}{amount}\mspace{14mu}{of}} \\{{ibuprofen}\mspace{14mu}{delivered}\mspace{14mu}{from}\mspace{14mu}{test}} \\{{formulation}\mspace{14mu}\left( {\mu\; g\text{/}{cm}^{2}} \right)}\end{matrix}}{\begin{matrix}{{Mean}\mspace{14mu}{cumulative}\mspace{14mu}{amount}} \\{{of}\mspace{14mu}{ibuprofen}} \\{\mspace{14mu}{{delivered}\mspace{14mu}{from}\mspace{14mu}{Ibugel}\mspace{14mu}\left( {\mu\; g\text{/}{cm}^{2}} \right)}}\end{matrix}}$

For the purposes of this report, ER changes of less than 20% betweenformulations was considered to have no meaningful impact on permeabilitytrends.

Formulation Preparation

Typically, formulations used in the permeability experiments wereprepared as 5 to 10 g batches. The stability batches were prepared at100-g scale using the same general procedure described below.

The formulation components were added to a vial and vortexed until aclear solution was obtained. In case of formulations that containedmethyl and propyl paraben, these were added immediately after theibuprofen and before addition of DMSO. Only formulations that werehomogeneous by visual observation immediately prior to the permeabilityexperiments were included in these studies.

Formulation Development

Initial formulation activities for ibuprofen topical formulation werefocused on the development of various formulation types. During thedevelopment of these formulations, a stability concern arose related tothe formation of an ibuprofen related degradant, Compound A. It washypothesized that Compound A was the result of a reaction between thefree acid form of ibuprofen with ethanol to form the corresponding ethylester. Formulation and stability studies with the early formulationsindicated that the ester formation was pH-dependent with lower pHsshowing a higher rate of ester formation. The potential stabilitychallenges for ibuprofen in the presence of ethanol, especially atethanol concentrations of 30% or more, prompted exploratory activitiesto identify an alternative, foam formulation.

A comparator for foam formulation screening was the foamable diclofenacformulation. The ingredients of the foamable diclofenac formulation areprovided in Table 22. See also Example 1.

TABLE 22 Composition of DMSO Base Foam Formulation Component Diclofenacsodium Ethanol Propylene glycol Dimethylsulfoxide (DMSO) Glycerin WaterBrij 30 Brij 78 Cholesterol Sodium laureth sulfate (SLES)

Example 14 Effect of Sodium Carbonate on the Permeability of Ibuprofen

Sodium carbonate was added to the formulation to control the pH of theformulation (Table 23). Initially, 0.5% of sodium carbonate was added tothe formulation, as this was estimated to raise the pH of theformulation to 6.0. All formulations contained 0.1% cholesterol as afoam stabilizing agent and the concentration of Brij 30 was maintainedat 1.3%. The effect of addition of sodium carbonate to the formulationwas studied in combination with each of the anionic surfactants SLS andSLES. The procedures set forth in Example 13 were used for theevaluation.

TABLE 23 Effect of Sodium Carbonate on the Permeability of Ibuprofenfrom Foam Formulations) Component Ibu Ibu Ibu Ibu (wt %) Ibugel100802-01 100802-02 100802-03 100802-04 Ibuprofen 5.0 5.0 5.0 5.0 5.0DMSO 28.7 28.7 28.7 28.7 Water 43.7 44.2 43.7 44.2 Ethanol 7.4 7.4 7.47.4 Propylene 7.1 7.1 7.1 7.1 Glycol Glycerin 4.9 4.9 4.9 4.9 Brij 301.3 1.3 1.3 1.3 Cholesterol 0.1 0.1 0.1 0.1 SLS 1.3 1.3 0 0 Sodium 0.5 00.5 0 carbonate SLES 0 0 1.3 1.3 Cum amt 45.57 112.83 104.09 104.71110.49 transported at 24 h (μg/cm2) (Mean) SEM 11.83 12.41 10.14 2.4217.22 ER 1.0 2.48 2.28 2.30 2.42

The results are shown in FIG. 56. A two-fold increase in ibuprofendelivery at 24 h as compared to Ibugel was achieved for all theformulations tested. No trends were observed for permeability ofibuprofen in presence of sodium carbonate (Ibu 100802-01 vs. Ibu100802-02 and Ibu 100802-03 vs. Ibu 100802-04)). Based on the cumulativeamount transported at 24 h after dose application, the delivery ofibuprofen from formulations containing either SLS or SLES as the anionicsurfactant was comparable (100802-01 vs. Ibu 100802-03). The type ofanionic surfactant used appeared to have no impact on the delivery ofibuprofen.

Example 15 Effect of Thickening Agent and Reduction of Total SurfactantConcentration on the Permeability of Ibuprofen

Cholesterol was eliminated from the formulation and the followingchanges were evaluated: addition of 2% HPC(HPC HY 121) as a thickeningagent; influence of the type of anionic surfactant (SLS vs. SLES); andthe effect of reducing the total surfactant concentration from 2.6% to1.3% (Table 24). The procedures set forth in Example 13 were used forthe evaluation.

TABLE 24 Effect of Thickening Agent and Reduction of Total Surfactant onthe Permeability of Ibuprofen Component Ibu Ibu 100810- Ibu 100810- Ibu100810- Ibu 100810- (wt %) Ibugel 100810-01 02 03 05 06 Ibuprofen 5.05.0 5.0 5.0 5.0 5.0 DMSO 28.7 28.7 28.7 28.7 28.7 Water 41.8 42.3 41.845.1 45.1 Ethanol 7.4 7.4 7.4 7.4 7.4 Propylene 7.1 7.1 7.1 7.1 7.1Glycol Glycerin 4.9 4.9 4.9 4.9 4.9 Brij 30 1.3 1.3 1.3 0 1.3Cholesterol 0 0 0 0 0 SLS 1.3 1.3 0 1.3 0 Sodium 0.5 0 0.5 0.5 0.5carbonate SLES 0 0 1.3 0 0 HPC HY 121 2.0 2.0 2.0 0 0 Cum amt 21.62100.42 117.31 101.50 118.80 154.87 transported at 24 h (μg/cm2) SEM 2.847.32 4.84 6.95 8.31 13.22 ER 1.00 4.65 5.43 4.70 5.5 7.16

The results are shown in FIG. 57. A four- to seven fold increase inibuprofen delivery as compared to Ibugel was achieved with all theformulations. Addition of 2% HPC (HY 121) as a thickening agent toformulations containing sodium carbonate (100810-01 vs. 100810-02) didnot seem to impact the permeability of ibuprofen. The type of anionicsurfactant used (SLS or SLES) did not seem to impact the permeability ofibuprofen from formulations containing a thickening agent (100801-01 vs.100801-03). Reducing the total surfactant concentration from 2.6% to1.3% by eliminating non-ionic surfactant Brij 30 did not seem to affectthe permeability of ibuprofen from the formulations (100810-01 vs.100810-05). Reducing the total surfactant concentration from 2.6% to1.3% by eliminating the anionic surfactant SLS may have improvedpermeation of ibuprofen from the formulations (100810-01 vs. 100810-06).

Example 16 Effect of Surfactants in the Formulation on the Permeabilityof Ibuprofen

I: Brij 78

Experiments were conducted to understand the effects of surfactant type,total surfactant concentration and ratio of surfactants on thepermeability of ibuprofen from the test formulations. The procedures setforth in Example 13 were used for the evaluation.

An additional non-ionic surfactant, 1% Brij 78, was added to all theformulations (Table 25). For formulations 1000802-1 to 1000802-4, 1.3%Brij 30 was also added to maintain the non-ionic surfactantconcentration 2.3%, while either SLS or SLES was used at 2%concentration to maintain the total surfactant (non-ionic+anionicsurfactant) concentration at 4.3%. These formulations also contained0.1% cholesterol.

The effect of removal of glycerin on the permeability of ibuprofen wasinvestigated with formulations 4-F1, 4-F2, and 4-F3. In theseformulations, cholesterol was removed, 2% SLS and 1% SLES were addedwhile the Brij 78 concentration was maintained at 1% and Brij 30 levelwas reduced to 0.1%. In addition, the ethanol level was increased from7.4% to 11.2%.

TABLE 25 Effect of Addition of Brij 78, Increased Ethanol, and Removalof Glycerine on Permeability of Ibuprofen Ibu Ibu Ibu Component Ibu IbuIbu Ibu 100802-4- 100802- 100802- (wt %) Ibugel 100802-1 100802-2100802-3 100802-4 F1 4-F2 4-F3 Ibuprofen 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0DMSO 28.7 28.7 28.7 28.7 29.7 29.7 29.7 Water 43.7 44.2 43.7 44.2 37.336.8 41.9 Ethanol 7.4 7.4 7.4 7.4 11.2 11.2 11.2 Propylene 7.1 7.1 7.17.1 7.3 7.3 7.3 Glycol Glycerin 4.9 4.9 4.9 4.9 5.0 5.1 0 Brij 30 1.31.33 1.3 1.33 0.1 0.1 0.1 Cholesterol 0.1 0.1 0.1 0.1 0 0 0 SLS 2.0 2.00 0 2.0 2.0 2.0 Sodium 0.5 0 0.5 0 0 0.5 0.5 carbonate SLES 0 0 2 2 1 11 Brij 78 1 1 1 1 1 1 1 Cum amt 23.54 66.40 80.62 74.66 77.10 64.0970.04 62.08 transported at 24 h (μg/cm2) SEM 4.51 13.54 13.49 9.94 14.1914.49 9.41 6.74 ER 1.00 2.82 3.43 3.17 3.28 2.72 2.98 2.64

The results are shown in FIG. 58. A two- to three fold increase inibuprofen delivery compared to Ibugel was achieved for all theformulations. The type of anionic surfactant used (SLS or SLES) did notseems to have a measurable impact on permeability (100802-1 vs.100802-4). The delivery of ibuprofen from the formulations containingeither of the anionic surfactants did not seem to be impacted by thepresence or absence of sodium carbonate (100802-1 vs. 100802-2 and100802-3 vs. 10802-4). For the formulations containing 11.2% ethanol,the presence or absence of sodium carbonate in the formulation seemed tohave no impact on permeability (100802-4-F1 vs. 100802-4-F2). For theformulations containing 11.2% ethanol, the removal of glycerin seemed tohave no impact on the permeability of ibuprofen (100802-4-F2 vs.100802-4-F3).

Example 17 Effect of Surfactants in the Formulation on the Permeabilityof Ibuprofen

II: Anionic Surfactants

Experiments were conducted to understand the effects of surfactant type,total surfactant concentration and ratio of surfactants on thepermeability of ibuprofen from the test formulations. The procedures setforth in Example 13 were used for the evaluation.

The non-ionic surfactants were maintained constant at 2%, while thetotal concentration of the anionic surfactant combination was variedfrom 1 to 2%, both in presence and absence of cholesterol (Table 26).The ratio of the anionic surfactants, SLS to SLES was also varied withinthe formulations.

TABLE 26 Effect of Anionic Surfactant Ratio and Total SurfactantConcentration Ibu Ibu Ibu Ibu Ibu Ibu Ibu Ibu Component 100816- 100816-100816- 100816- 100816- 100816- 100816- 100816- (wt %) Ibugel 19 20 2122 23 24 25 26 Ibuprofen 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 DMSO 28.128.5 28.3 28.3 28.1 28.4 28.4 28.4 Water 43.4 43.6 43.5 43.5 43.4 43.543.5 43.5 Ethanol 7.3 7.4 7.3 7.3 7.3 7.3 7.3 7.3 Propylene 6.9 7.0 7.07.0 6.9 7.0 7.0 7.0 Glycol Glycerin 4.7 4.8 4.8 4.8 4.8 4.8 4.8 4.8 Brij30 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Cholesterol 0.1 0.1 0.1 0.1 0 0 0 0.1SLS 1 0.5 0.5 1 1 0.5 1 1 Sodium 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5carbonate SLES 1.0 0.5 1.0 0.5 1.0 1.0 0.5 0 Brij 78 1.0 1.0 1.0 1.0 1.01.0 1.0 1.0 Cum amt 27.54 56.50 58.72 68.83 52.66 56.29 63.55 53.8675.55 transported at 24 h (μg/cm2) SEM 18.52 18.75 16.09 20.82 19.8716.32 12.21 12.42 11.36 ER 1.00 2.05 2.13 2.5 1.9 2.04 2.31 1.96 2.74

The results are shown in FIG. 59. A two-fold increase in ibuprofendelivery as compared to Ibugel was observed for all formulations tested.In the presence of 0.1% cholesterol, varying the total anionicsurfactant concentration to 1%, 1.5%, or 2% seemed to have a negligibleeffect on the permeability of ibuprofen, irrespective of the ratio ofSLES to SLS (Ibu 100816-19 to Ibu 100816-22). In the absence ofcholesterol, varying the total anionic surfactant concentration to 1%,1.5%, or 2% seemed to have a negligible effect on the permeability ofibuprofen, irrespective of the ratio of SLES to SLS (Ibu 100816-23 toIbu 100816-25). A slight increase in permeability was observed when SLESwas removed from the anionic surfactant combination (Ibu 100816-26).

Example 18 Effect of Surfactants in the Formulation on the Permeabilityof Ibuprofen

III: Non-ionic Surfactants

Experiments were conducted to understand the effects of surfactant type,total surfactant concentration and ratio of surfactants on thepermeability of ibuprofen from the test formulations. The procedures setforth in Example 13 were used for the evaluation.

A single anionic surfactant SLS was used and the concentration of SLSwas maintained constant at either 1% or 1.3%, while the effect ofchanging non-ionic surfactant concentration was studied (Table 27). Theobjective of the experiment was to explore the possibility of reducingthe total surfactant levels in the formulation.

TABLE 27 Effect of Non-ionic Surfactant Concentration on Permeability ofIbuprofen Ibu Ibu Ibu Ibu Ibu Ibu Ibu Component 100816- 100816- 100816-100816- 100816- 100816- 100816- (wt %) Ibugel 10 11 12 14 15 16 17Ibuprofen 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 DMSO 28.7 29.4 28.8 28.5 29.029.0 28.6 Water 43.7 43.9 43.7 43.6 43.8 43.8 43.6 Ethanol 7.4 7.6 7.57.4 7.5 7.5 7.4 Propylene 7.1 7.2 7.1 7.0 7.1 7.1 7.0 Glycol Glycerin4.9 5.0 4.9 4.8 4.9 4.9 4.8 Brij 30 1.3 0 1.3 1 1 0 1 Cholesterol 0.10.1 0 0.1 0.1 0.1 0 SLS 1.3 1.3 1.3 1 1 1 1 Sodium 0.5 0.5 0.5 0.5 0.50.5 0.5 carbonate Brij 78 0 0 0 1 0 1 1 Cum amt 14.42 86.97 97.92 107.50124.43 120.83 88.85 111.87 transported at 24 h (μg/cm2) SEM 3.44 21.5220.22 21.48 17.01 18.83 23.39 21.93 ER 1.00 6.03 6.79 7.46 8.63 8.386.16 7.76

The results are shown in FIG. 60. A six to eight fold increase indelivery of ibuprofen as compared to Ibugel was observed for allformulations. Lowering the total concentration of surfactants in theformulation to 1.3% or 2% by decreasing the concentration of non ionicsurfactants did not seem to impact the permeability of ibuprofen.

Example 19 Effect of Surfactants in the Formulation on the Permeabilityof Ibuprofen

IV: Reduced Surfactant Concentration

Experiments were conducted to understand the effects of surfactant type,total surfactant concentration and ratio of surfactants on thepermeability of ibuprofen from the test formulations. The procedures setforth in Example 13 were used for the evaluation.

The results of the experiments Examples 16, 17, and 18 indicated thatthe permeability of ibuprofen from the DMSO based formulation chassismay be independent of the surfactant concentration in the range of 1.3%to 4.3%. The results from the experiments conducted in Example 18demonstrated that a reduction in the total concentration of surfactantsappeared not to impact the permeability of ibuprofen. The following setof experiments were conducted using formulations without cholesterol toconfirm that the total concentration of surfactants in the formulationcould be reduced without significant impact on the permeability ofibuprofen (Table 28).

TABLE 28 Effect of Reduced Surfactant Concentration and Surfactant TypeComponent Ibu Ibu Ibu Ibu Ibu Ibu (wt %) Ibugel 100810-1 100810-2100810-3 100810-5 100810-7 100810-8 Ibuprofen 5.0 5.0 5.0 5.0 5.0 5.05.0 DMSO 28.7 28.7 28.7 45.5 28.7 28.7 Water 43.8 44.3 43.8 18.8 45.145.1 Ethanol 7.4 7.4 7.4 11.8 7.4 7.4 Propylene 7.1 7.1 7.1 11.2 7.1 7.1Glycol Glycerin 4.9 4.9 4.9 7.7 4.9 4.9 Brij 30 1.3 1.33 1.3 0 0 1.3Cholesterol 0 0 0 0 0 0 SLS 1.3 1.27 0 0 1.3 0 Sodium 0.5 0 0.5 0 0.50.5 carbonate SLES 0 0 1.3 0 0 0 Cum amt 34.01 65.68 86.04 89.97 79.7795.49 86.02 transported at 24 h (μg/cm2) SEM 10.37 14.40 13.17 11.8711.94 14.74 16.67 ER 1.00 1.93 2.53 2.65 2.35 2.81 2.53

The results are shown in FIG. 61. A two fold increase in the delivery ofibuprofen as compared to Ibugel was observed (except for formulation100810-1). The addition of sodium carbonate appeared to decrease thepermeability of ibuprofen when a combination of Brij 30 and SLS was used(formulation 100810-1). The reason for this decrease was unclear,particularly as previous experiments have indicated that the presence ofsodium carbonate did not seem to negatively impact the permeability ofibuprofen.

The type of anionic surfactant used in the formulation (SLS or SLES)seemed to have no impact on the permeability of ibuprofen. Acceptablelevels of ibuprofen transport could be obtained from formulations thatcontain only 1.3% of a single surfactant (100810-7 vs. 100810-8),confirming findings that the surfactant concentration in theformulations can be reduced without any impact to the permeability ofibuprofen. Acceptable levels of ibuprofen permeation could be obtainedwith formulations that do not contain surfactants or cholesterol, whenthe formulation contained DMSO at levels greater than 28% (Ibu100810-5).

Example 20 Effect of Surfactants in the Formulation on the Permeabilityof Ibuprofen

V: Non-ionic Surfactants

Experiments were conducted to understand the effects of surfactant type,total surfactant concentration and ratio of surfactants on thepermeability of ibuprofen from the test formulations. The procedures setforth in Example 13 were used for the evaluation.

Another round of formulations was conducted to confirm the need fornon-ionic surfactants in the formulation and to confirm the viability ofreduced surfactant concentration in the formulation (Table 29).

TABLE 29 Effect of Non-Ionic Surfactants on Delivery of IbuprofenComponent Ibu Ibu Ibu Ibu Ibu Ibu (wt %) Ibugel 100816-1 100816-2100816-3 100816-5 100816-7 100816-8 Ibuprofen 5.0 5.0 5.0 5.0 5.0 5.05.0 DMSO 28.7 29.4 28.8 28.5 29.0 28.6 Water 43.7 43.9 43.7 43.6 43.843.6 Ethanol 7.4 7.6 7.5 7.4 7.5 7.4 Propylene 7.1 7.2 7.1 7.0 7.1 7.0Glycol Glycerin 4.9 5.0 4.9 4.8 4.9 4.8 Brij 30 1.3 0 1.3 1.0 0 1.0Cholesterol 0.1 0.1 0 0.1 0.1 0 SLES 1.3 1.3 1.3 1.0 1.0 1.0 Sodium 0.50.5 0.5 0.5 0.5 0.5 carbonate Brij 78 0 0 0 1.0 1.0 1.0 Cum amt 13.9563.35 66.78 75.83 50.67 52.20 47.29 transported at 24 h (μg/cm2) SEM2.58 11.46 6.35 12.29 5.29 7.62 2.90 ER 1.00 4.54 4.79 5.44 3.63 3.743.39

The results are shown in FIG. 62. A three to five fold increase inibuprofen delivery as compared to Ibugel was observed from theformulations. Reduction of total surfactant concentration from 2.6% to1.3% by removal of Brij 30 proved unlikely to impact the permeability ofibuprofen (100816-1 vs 100816-2). Removal of cholesterol from theformulation containing 2.6% total surfactant proved unlikely to impactthe permeability of ibuprofen (100816-1 vs 100816-3). Increasing thesurfactant concentration to 3%, by the addition of Brij 78 proved likelyto negatively impact the permeability of ibuprofen (100816-1 vs.100816-5 and 100816-8). The results confirmed findings that acombination of anionic surfactant with non-ionic surfactant appearedlikely to provide a suitable formulation from an ibuprofen deliveryperspective.

Example 21 Effect of Surfactants in the Formulation on the Permeabilityof Ibuprofen

VI: Brij 78

Experiments were conducted to understand the effects of surfactant type,total surfactant concentration and ratio of surfactants on thepermeability of ibuprofen from the test formulations. The procedures setforth in Example 13 were used for the evaluation.

The effect of varying concentrations of non-ionic surfactant Brij 78 wasstudied in combination with either one of the anionic surfactant SLS orSLES (Table 30). Brij 30 concentration was maintained at 1% for all theformulations, and the cholesterol level was varied from 0.1 to 0.2%.

TABLE 30 Effect of Brij 78 Levels on the Permeability of Ibuprofen IbuComponent Ibu 100826- Ibu 100826- Ibu 100826- Ibu 100826- 100826-01 wt %Ibugel 01 02 03 04 (2) Ibuprofen 5.0 5.0 5.0 5.0 5.0 5.0 DMSO 28.7 28.728.7 28.7 28.7 Water 43.9 42.9 43.9 42.9 44.3 Ethanol 7.4 7.4 7.4 7.47.4 Propylene 7.1 7.1 7.1 7.1 7.1 Glycol Glycerin 4.9 4.9 4.9 4.9 4.9Brij 30 1.0 1.0 1.0 1.0 1.0 Cholesterol 0.2 0.2 0.2 0.1 0.1 SLS 0 0 0.30.3 0 Sodium 0.5 0.5 0.5 0.5 0.5 carbonate SLES 0.3 0.3 0 0 0 Brij 781.0 2.0 1.0 2.0 1.0 Cum amt 8.24 56.14 42.86 67.43 63.81 76.08transported at 24 h (μg/cm2) SEM 1.34 4.27 4.30 4.64 5.30 23.7 ER 1.006.81 5.20 8.18 7.74 9.23

The results are shown in FIG. 63. A five- to nine-fold enhancement inthe delivery of ibuprofen as compared to Ibugel was observed for theformulations tested. For formulations containing 0.2% cholesterol andSLES, increasing the Brij 78 concentration to 2% apparently decreasedthe permeability of ibuprofen (100826-02). For formulations containing0.2% cholesterol and SLS, increasing the Brij 78 concentration to 2%seemed to have no impact on the permeability of ibuprofen (100826-03 and100826-04). There appeared to be a trend towards higher permeability ofibuprofen from formulations that contain a surfactant combination of SLSand Brij 78, as compared to formulations that contain a surfactantcombination of Brij 78 and SLES. (100826-01 vs 100826-03 and 100826-02vs 100826-04). The results confirmed earlier findings that removal ofanionic surfactants appeared unlikely to impact the permeability ofibuprofen from DMSO based formulations.

Example 22 Effect of Cholesterol Levels on Permeability of Ibuprofenfrom DMSO-Based Formulations

Based on the results of the previous experiments that demonstrate thatpermeability of ibuprofen from DMSO based formulations showed lowsensitivity to surfactant concentrations in the formulations,experiments to evaluate the effect of varying cholesterol levels from 0to 0.4% was determined using the formulations with reduced surfactantlevels (Table 31). The procedures set forth in Example 13 were used forthe evaluation.

TABLE 31 Effect of Cholesterol Levels on Permeability of Ibuprofen IbuIbu Ibu Ibu Ibu Ibu Ibu Ibu Ibu Ibu Component 100823- 100823- 100823-100823- 100823- 100823- 100823- 100823- 100823- 100823- (wt %) Ibugel 0102 04 05 06 07 08 09 10 11 Ibuprofen 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.05.0 5.0 DMSO 28.7 28.7 28.7 28.7 28.7 28.7 28.7 28.7 28.7 28.7 Water32.4 32.5 32.4 32.35 32.3 32.2 32.25 32.1 31.9 31.4 Ethanol 7.4 7.4 12.37.4 7.4 7.4 7.4 7.4 7.4 7.4 Propylene 7.1 7.1 7.1 7.1 7.1 7.1 7.1 7.17.1 7.1 Glycol Glycerin 4.9 4.9 0 4.9 4.9 4.9 4.9 4.9 4.9 4.9 Brij 301.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Cholesterol 0.1 0 0.1 0.15 0.20.3 0.4 0.1 0.1 0.1 (Note that dissolution of cholesterol in theformulation at concentration s >0.1% is challenging) SLS 0 0 0 0 0 0 0 00 0 Sodium 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0 carbonate SLES 0 0 0 00 0 0.15 0.3 0.5 0.5 Brij 78 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Cumamt 4.65 61.0 73.93 54.47 52.56 87.36 66.44 60.84 76.44 69.77 63.25transported at 24 h (μg/cm2) SEM 1.78 4.42 9.40 10.05 3.31 8.58 7.377.94 6.09 9.71 8.34 ER Not calculated

The results are shown in FIG. 64. Based on the cumulative amount ofibuprofen transported at 24 h, it seemed likely that cholesterol levelshave no impact on permeability of ibuprofen. Control Ibugel formulationexhibited considerably lower than normal values for delivery ofibuprofen (approximately 10% of normal values) and appears to be outsidethe range of normally observed values. Therefore, ER was not calculatedfor this experiment.

Example 23 Evaluation of Water-Based Formulation (No AdditionalSolvents)

The permeability of ibuprofen from a water based formulation containingno solvents was compared to a DMSO based formulation (Table 32). Theprocedures set forth in Example 13 were used for the evaluation.

TABLE 32 Effect of Water Based Formulation on Permeability of Ibuprofen)Component wt % Ibugel Ibu 100823-X Ibu 100802-4 Ibuprofen 5.0 5.0 5.0DMSO 0 28.74 Water 90.65 44.18 Ethanol 0 7.45 Propylene 0 7.07 GlycolGlycerin 0 4.86 Brij 30 1 1.33 Cholesterol 0.1 0.1 SLES 0 1.27 Sodium1.25 0 carbonate Brij 78 2 0 Cum amt 13.95 20.01 39.59 transported at 24h (μg/cm2) SEM 2.58 9.96 7.15 ER 1.00 1.43 2.84

The results are shown in FIG. 65. The DMSO-free formulation failed toprovide a two-fold delivery enhancement over that of Ibugel (100823-X).Based on the differences in ER, it appeared that a DMSO-free,water-based formulation seemed unlikely to meet the permeabilityperformance characteristics needed for the product. The DMSO basedformulation (Ibu 100802-4) met the target permeability characteristicsrequired for the ibuprofen foam formulation.

Example 24 Evaluation of a Water-Based Formulation Containing ThickeningAgents and Poloxamer 407

Additional work was conducted with water-based formulations to determineif the addition of hydropropyl cellulose (HPC HY 121 and HPC HY 117)would improve the delivery characteristics from this formulation (Table33). The experiment also evaluated whether the combination of Poloxamer407 and polyvinyl alcohol (PVA) impacte the permeability of ibuprofenfrom water-based formulations. The procedures set forth in Example 13were used for the evaluation.

TABLE 33 Effect of Thickening Agents and Poloxamer 407 on thePermeability of Ibuprofen Ibu Ibu Ibu Ibu Component 100823- 100823-100823- 100823- wt % Ibugel X1 X2 X3 X4 Ibuprofen 5.0 5.0 5.0 5.0 5.0Brij 30 1.0 1.0 1.0 1.0 Brij 78 2.0 2.0 2.0 2.0 Cholesterol 0.1 0.1 0.10 Sodium 1.25 1.0 1.0 1.25 carbonate Water 90.65 88.9 88.9 88.5 HPC HY121 0 2 0 0 HPC HY 117 0 0 2.0 0.25 PVA 0 0 0 1.5 Poloxamer 407 0 0 00.5 Cum amt 19.23 18.61 19.29 13.37 17.98 transported at 24 h (μg/cm2)SEM 3.85 8.899 4.86 6.48 6.09 ER 1.00 0.97 1.00 0.70 0.93

The results are shown in FIG. 66. The water based formulationscontaining thickening agents failed to demonstrate any deliveryenhancement for ibuprofen. Ibuprofen permeability from water basedformulations do not meet expectations for an ibuprofen topical foamformulation. The formulation containing a combination of PVA andPoloxamer 407, though capable of forming acceptable foams, failed toprovide the necessary delivery enhancement.

Example 25 Evaluation of Ethanol-Free DMSO-Based Formulations

The development of an ethanol-free DMSO-based formulation was ofinterest in eliminating the formation of ibuprofenesterification-related degradant (Table 34). In addition, the overallreduction and minimization of DMSO in the formulation was of interest inthe context of minimizing excipients. The procedures set forth inExample 13 were used for the evaluation.

The DMSO content was varied from 15% to 45.5% in formulations withoutethanol, propylene glycol, and glycerin. Glycerin was eliminated fromthe formulation, to test its impact on the drying time of the foam uponapplication to the skin.

For formulations Ibu 1008025-05 to 1008025-07, 7.1% propylene glycol wasincluded in the formulations. The concentration of Brij 30 wasmaintained at 1%, cholesterol was maintained at 0.1%, and Brij 78 wasmaintained at 1%, except for a formulation at 2% (100825-02). Anionicsurfactants were removed from the formulation to evaluate whetheracceptable formulations could be obtained with only non-ionicsurfactants.

TABLE 34 Effect of Varying DMSO Content on the Permeability of IbuprofenIbu Ibu Ibu Ibu Ibu Ibu Ibu Component 100825- 100825- 100825- 100825-100825- 100825- 100825- wt % Ibugel 01 02 03 04 05 06 07 Ibuprofen 5.05.0 5.0 5.0 5.0 5.0 5.0 5.0 DMSO 28.7 28.7 45.5 15.0 45.5 28.7 15.0Water 63.7 62.7 46.9 77.4 39.8 56.6 70.3 Ethanol 0 0 0 0 0 0 0 Propylene0 0 0 0 7.1 7.1 7.1 Glycol Glycerin 0 0 0 0 0 0 0 Brij 30 1.0 1.0 1.01.0 1.0 1.0 1.0 Cholesterol 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Sodium 0.5 0.50.5 0.5 0.5 0.5 0.5 carbonate Brij 78 1.0 2.0 1.0 1.0 1.0 1.0 1.0 Cumamt 17.04 47.44 54.83 88.51 47.09 126.48 70.47 62.75 transported at 24 h(μg/cm2) SEM 4.06 5.70 5.91 7.58 4.79 7.72 8.83 7.50 ER 1.00 2.78 3.225.19 2.76 7.42 4.13 3.68

The results are shown in FIG. 67. A two- to seven-fold increase in thedelivery of ibuprofen as compared to Ibugel was observed, dependent onformulation composition. In formulations without ethanol, glycerin orpropylene glycol, increasing the DMSO content from 15% to 28.7% did notappear to have a meaningful impact on permeability (100825-04 and100825-01). Increasing the concentration of DMSO to 45.5% seemed likelyto have a positive impact on permeability of ibuprofen (100825-03) fromformulations without ethanol, glycerine or propylene glycol.

In formulations containing 7.1% propylene glycol but without glycerin orethanol, raising the DMSO levels from 15% to 28.7% did not appear tohave a meaningful impact on permeability. Increasing the DMSO content to45.5% in these formulations is likely to have a positive impact on thepermeability of ibuprofen.

Increasing the concentration of Brij 78 to 2% in the formulationscontaining 28.7% DMSO seems unlikely to impact the permeability ofibuprofen. Although the formulations containing 45.5% DMSO provided thehighest delivery enhancement, lowering DMSO levels should provide moredesirable foam characteristics.

Example 26 Effects of Varying Ethanol and Glycerine Levels on thePermeability of Ibuprofen

The effect of varying levels of ethanol in formulations (0, 7.45%, and11.2% ethanol at ˜28% DMSO; and 0% ethanol at 15% DMSO) with or withoutglycerin were studied (Table 35A and B). The type and concentration ofanionic surfactants were also varied. The objective of these experimentswas to determine if glycerine and the anionic surfactants are criticalto the performance of the formulation, primarily intended to minimizeexcipients in the formulation. The procedures set forth in Example 13were used for the evaluation.

TABLE 35 Effect of Varying Ethanol and Glycerin Levels Ibu Ibu Ibu IbuComponent 100802- 100802- 100825- 100825- wt % Ibugel 01 04-F2 06 07Ibuprofen 5.0 5.0 5.0 5.0 5.0 DMSO 28.74 29.69 28.7 15.0 Water 43.6836.8 56.6 70.3 Ethanol 7.45 11.2 0 0 Propylene 7.07 7.31 7.1 7.1 GlycolGlycerin 4.86 5.07 0 0 Brij 30 1.3 1.0 1.0 1.0 Cholesterol 0.1 0.1 0.10.1 SLS 1.3 0 0 0 Sodium 0.5 0.5 0.5 0.5 carbonate SLES 0 2.0 0 0 Brij78 0 1.0 1.0 1.0 Cum amt 8.10 51.44 46.16 21.49 20.65 transported at 24h (μg/cm2) SEM 1.75 7.36 6.42 2.10 2.55 ER 1.00 6.35 5.70 2.65 2.55

TABLE 35B Effect of Varying Ethanol and Glycerin Levels II Component (wt%) Ibu 100818-08 F11 Ibuprofen 5.0 Amphosol 2.73 Ethanol 16.39Transcutol 10.93 Lactic Acid 0 Water 60.80 TEC 0 Brij 30 1 Brij 78 1Cholesterol 0.15 Sodium carbonate 1.0 SLES 1.0 Cum amt 6.69 transportedat 24 h (μg/cm2) SEM 1.54 ER 0.83

The results are shown in FIG. 68. For the DMSO based formulations,depending on formulation type, a two- to six-fold increase in deliveryof ibuprofen as compared to Ibugel was observed. Increasing ethanolconcentrations from 7.45% to 11.2% while maintaining DMSO concentrationat ˜28% and glycerin at ˜5% appeared to have no impact on thepermeability of ibuprofen (100802-01 vs. 100802-04-F2). Complete removalof ethanol and glycerin from the formulation while maintaining DMSOlevels at 28% may have the effect of decreasing the permeability ofibuprofen (100825-06). The comparable ER observed for formulations100825-06 and 100825-07 indicated that the delivery of ibuprofen may notbe influenced by DMSO levels in the range of 15 to 28.7%. The removal ofanionic surfactants from the formulation was feasible without impactingibuprofen delivery characteristics.

Example 27 pH Stability of DMSO-Based Formulations

In order to confirm the pH stability of DMSO formulations, the followingformulations were prepared and maintained at 67.6° C. for 1 week (Table36).

TABLE 36 Composition of Formulations Prepared for pH Study Ibu Ibu IbuIbu Component 100802- 100802- 100802- 100802- wt % 4-F1 4-F2 4-F3 01Ibuprofen 5.0 5.0 5.0 5.0 DMSO 29.7 29.7 29.7 28.7 Water 37.3 36.8 41.943.7 Ethanol 11.5 11.5 11.5 7.4 Propylene 7.3 7.3 7.3 7.1 GlycolGlycerin 5.0 5.1 0 4.9 Brij 30 1.0 1.0 1.0 1.3 Cholesterol 0.1 0.1 0.10.1 SLS 0 0 0 2.0 Sodium 0 0.5 0.5 0.5 carbonate SLES 2.0 2.0 2.0 0 Brij78 1.0 1.0 1.0 1.0 pH at T = 0 4.71 6.65 6.61 6.48 pH at T = 7 d 4.396.67 6.65 6.46 (storage at 67.6° C.)

pH measurements indicated no changes to the pH of the formulations overa period of 7 days under the conditions studied.

Example 28 Selection and Properties of Ibuprofen Foam Formulations:Selection Conclusions from Formulation Screening Activities

The overall conclusions from the formulation screening studies describedabove may be summarized as follows.

-   -   The degree of enhancement of ibuprofen delivery from DMSO based        formulations is dependant on the concentration of DMSO in the        formulations.    -   Two-fold enhancement in delivery of ibuprofen over comparator        Ibugel is feasible for ethanol-containing and ethanol-free,        DMSO-based formulation.    -   The permeation of ibuprofen from DMSO-based formulations is        likely to be independent of the surfactant concentration;        however, the presence of surfactants may be advantageous in        producing acceptable foam characteristics.    -   The use of thickening agents, such as HPC HY 121, is unlikely to        impact the permeability of ibuprofen from DMSO based        formulations.        Selection of Ibuprofen Foam Formulations

The formulation development activities described in the previousexamples led to the identification of the following types of formulationchassis for the ibuprofen foamable formulations:

1. DMSO based formulations containing ethanol and glycerin, e.g.,100826-01 (02); and

2. DMSO based formulations without ethanol and glycerine, e.g.,100825-07.

In general, the DMSO based formulations provide greater than two-foldenhancement in the delivery of ibuprofen. Both formulation types wereincluded in the stability studies.

Formulation variations for the above-described formulation chassis weremanufactured at the 100 g scale and tested for stability. Table 37provides the composition of the formulations that were tested forstability.

TABLE 37 Composition of Formulations Selected for Stability Studies100825- 100825- 100826- 100826- 100826- 100826- 100826- 100826- 06 07 0102 03 04 05 06 (9210) (9210) (9310) (9310) (9310) (9310) (9310) (9310)Ibuprofen 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 DMSO 28.7 15.0 28.74 28.7428.74 28.74 28.74 28.74 Water 55.3 68.8 43.88 42.88 43.58 42.88 43.9843.14 Ethanol 0 0 7.45 7.45 7.45 7.45 7.45 7.45 Propylene 7.1 7.1 7.077.07 7.07 7.07 7.07 7.07 Glycol Glycerin 0 0 4.86 4.86 4.86 4.86 4.864.86 Brij 30 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Cholesterol 0.1 0.1 0.2 0.20.2 0.2 0.1 0.2 SLS 0 0 0 0 0.3 0.3 0 0 Sodium 0.75 1.0 0.5 0.5 0.75 0.50.75 0.5 carbonate SLES 0 0 0.3 0.3 0 0 0 0 Brij 78 2.0 2.0 1.0 2.0 1.02.0 1.0 2.0 pH (T = 0) 7.04 7.06 6.69 6.70 6.71 6.71 6.95 6.72

Example 29 Selection and Properties of Ibuprofen Foam Formulations:Permeation Study Results

The formulations tested are described in Example 28. Table 38 provides asummary of the ibuprofen delivery characteristics of the variousformulations tested for stability. The permeation characteristics of theformulations at T=0 months were evaluated using the experimentalprocedures discussed in Example 13. All permeation experiments wereconducted using dermatomed porcine skin.

TABLE 38 Summary of Ibuprofen Delivery from Formulations Used forStability Studies 100825- 100825- 100826- 100826- 100826- 100826-100826- 100826- 100831- 100831- 06 07 01 02 03 04 05 06 04 01 (9210)(9210) (9310) (9310) (9310) (9310) (9310) (9310) (9210) (9210) Cum amt60.6 37.3 81.9 69.7 96.8 88.3 97.2 90.0 39.6 27.5 transported at 24 h(ug/cm2) SEM 6.7 2.8 7.0 4.2 6.5 7.7 14.0 7.9 9.9 2.8 ER 3.41 2.10 3.753.19 4.43 4.04 4.45 4.12 2.18 1.51

The results are shown in FIGS. 69-71. A two- to four-fold increase inthe delivery of ibuprofen was observed at 24 h for all the DMSO basedformulations (100825 and 100826 series).

Example 30 Selection and Properties of Ibuprofen Foam Formulations:Stability Study Results

The formulations tested are described in Example 28. For the stabilitystudy, the formulations were stored in glass vials at 25° C., 40° C. and70° C. The samples at 25° C. and 40° C. will be analyzed for pH,ibuprofen concentration, total impurities and Compound A at T=0, T=1,and T=3 months, while the 70° C. samples were tested at T=0, 9, 17, and27 days of storage. A summary of the data is presented in Table 39.

TABLE 39 Formulation Stability After 3 Months at 25° C. and 40° C. 25°C. storage condition 40° C. storage condition Total Total FormulationIBU Compound impurities IBU Compound impurities ID (%) A (%) (%) ΔpH (%)A (%) (%) ΔpH 100825-06 99.8 0.00 0.19 −0.04 99.2 0.00 0.13 −0.03100825-07 100.2 0.00 0.05 0.11 100.6 0.00 0.06 0.12 100826-01 99.0 0.330.41 0.02 98.2 0.96 0.14 0.01 100826-02 97.8 0.31 0.42 0.09 97.8 0.950.12 0.03 100826-03 99.2 0.31 0.40 −0.05 98.8 0.91 0.13 −0.06 100826-0499.2 0.29 0.42 −0.02 98.8 0.90 0.06 −0.02 100826-05 98.4 0.12 0.28 0.0298.6 0.37 0.17 −0.01 100826-06 99.0 0.34 0.43 0.05 98.8 1.04 0.17 0.04100831-01 98.6 0.19 0.42 0.01 98.8 0.62 0.27 0 100831-02 99.0 0.50 0.53−0.05 98.8 1.53 0.42 −0.06

Results indicated that all ten formulations indicate excellent stabilityfor ibuprofen content as well as pH of the formulations. The presence ofCompound A was not observed in the ethanol-free formulations 100825-06and 100825-07 consistent with the hypothesis that Compound A is theethyl ester of ibuprofen. Formulations in the 100826 series andformulations 100831-01 and 100831-04 indicate the presence of CompoundA; on par with the production of the degradant in gel formulationscontaining TEC. The stability results indicate that the primary factorscontrolling the rate of production of Compound A were pH of formulationand the concentration of ethanol (decreasing concentration of Compound Aproduced with increasing pH and ethanol content).

Based on the stability data available, the lowest levels of Compound Aand total impurities were observed in formulation 100825-07 andformulation 100826-05. The ethanol free formulation 100825-07 wasexpected to provide maximum optimal stability of ibuprofen, and theethanol containing formulation 100826-05 was predicted to have thelowest rate of esterification of ibuprofen due to its higher pH value.

Example 31 Selection and Properties of Ibuprofen Foam Formulations: SkinIrritation Study Results

The formulations tested are described in Example 28. Concurrent with thestability studies, two DMSO-based foam formulations were tested for skinirritation using the EpiSkin® test model (In Vitro Assessment of theDermal Irritation Potential of Three Formulations Using the EpiSkin®Test System (Study conducted at Charles River, Edinburgh, UK.).

In this study, the two formulations were tested in the SkinEthicEpiSkin® in vitro irritation assay using human keratinocytes derivedfrom healthy donors and grown in vitro to reconstruct a functional modelof the human epidermis. The results of the assay were similar for thetwo formulations and both were demonstrated to be non-irritants (nocategory) when tested in the EpiSkin® in vitro irritation assay.

Example 32 Ibuprofen Foam Formulations: Foam Stability Study

An additional set of ibuprofen formulations were prepared for foamstability testing. The composition of the formulations is set forth inTable 40.

TABLE 40 Formulation Compositions Formulation No. (Lot No.) IBU Brij 30Brij 78 PG GLY Na₂CO₃ EtOH H₂O DMSO  1 (F110128-1) 5 1 1 7.1 4.9 0.7518.06 18.06 44.14  2 (F110128-2) 5 1 1 7.1 4.9 0.75 0.00 36.11 44.14  3(F110128-3) 5 1 1 7.1 4.9 0.75 33.10 11.03 36.11  4 (F1101311) 5 1 1 7.14.9 0.75 11.03 33.10 36.11  5 (F110131-2) 5 1 1 7.1 4.9 0.75 26.08 26.0828.09  6 (F110131-3) 5 1 1 7.1 4.9 0.75 0.00 52.16 28.09  7 (F110131-4)5 1 1 7.1 4.9 0.75 45.14 15.05 20.06  8 (F110131-5) 5 1 1 7.1 4.9 0.7515.05 45.14 20.06  9 (F110131-6) 5 1 1 7.1 4.9 0.75 34.11 34.11 12.04 10(F110201-1) 5 1 1 7.1 4.9 0.75 0.00 68.21 12.04 11 (F110201-2) 5 1 1 7.14.9 0.75 57.18 19.06 4.01 12 (F110201-3) 5 1 1 7.1 4.9 0.75 19.06 57.184.01 13 (F110203-1) 5 1 1 7.1 4.9 0.75 10.03 10.03 60.19 14 (F110203-2)5 1 1 7.1 4.9 0.75 5.02 15.05 60.19 15 (F110203-3) 5 1 1 7.1 4.9 0.750.00 20.06 60.19 All compositions in % (w/w). IBU = ibuprofen; PG =propylene glycol; GLY = glycerol.

The foams were prepared by shaking in a calibrated cylinder for 10 secas described before or by use of a Rexam M3 foamining head. The resultsare set forth in Table 41, Table 42, and FIGS. 72 through 87.Formulations 2, 4, 6, 8, 10, 12, 13, 14 and 15 formed foams. However,formulation 2 produced a cloudy solution, formulation 10 included aprecipitate (FIG. 72), and formulation 13 produced a foam that was notfirmed and collapsed quickly. Formulations 1, 3, 5, 7, 9, and 11 did notproduce foams. Unlike ethanol, water and DMSO concentration variationdid not seem to have impact on the foam quality. For these formulations,the more ethanol that there was in the formulation, the lower the foam'squality, and the faster the foam's collapse.

TABLE 41 Formulation Observations I (Foaming Head/Foamer) FormulationNo. Formulation Foam Description Color of Foam Complete (Lot No.)Description at Initial Time at Initial Time Collapse Time 1 (F110128-1)Clear solution Not firm, a film of White 2 min 58 sec liquid around thefoam, with a lot of air bubbles 2 (F110128-2) Cloudy solution Foam witha lot of air White 17 min 45 sec  bubbles 3 (F110128-3) Clear solution Apseudo foam Whitish 25 sec (liquid) with a lot of air bubbles 4(F1101311)  Clear solution Firm, with a few air White 6 min 16 secbubbles 5 (F110131-2) Clear solution A pseudo foam Whitish 52 sec(liquid) with a lot of air bubbles 6 (F110131-3) Clear solution Firm,with a few air White 11 min bubbles 7 (F110131-4) Clear solution Apseudo foam Whitish 20 sec (liquid) with a lot of air bubbles 8(F110131-5) Clear solution Firm, with a few air White 8 min 30 secbubbles 9 (F110131-6) Clear solution A pseudo foam Whitish 1 min 17 sec(liquid) with a lot of air bubbles 10 (F110201-1)  Precipitation Firm,uniform, White 30 min without air bubbles 11 (F110201-2)  Clear solutionA pseudo foam Whitish 1 min 17 sec (liquid) with a lot of air bubbles 12(F110201-3)  Clear solution Firm, uniform, with a White 8 min 10 sec fewair bubbles 13 (F110203-1)  Clear solution Foam with a lot of White 7min 15 sec air bubbles 14 (F110203-2)  Clear solution More or lessuniform, White 8 min 10 sec without air bubbles 15 (F110203-3)  Clearsolution Firm, uniform, White 10 min 45 sec  without air bubbles

TABLE 42 Formulation Observations II (Shaker) Formulation No. (Lot No.)Height Complete Collapse Time Collapse Speed 1 (F110128-1) 3.2 cm 5 min30 sec 0.58 cm/min 2 (F110128-2) 2.2 cm 52 min 0.04 cm/min 3 (F110128-3)1.4 cm 1 min 41 sec 0.83 cm/min 4 (F1101311)  2.4 cm  5 min 0.48 cm/min5 (F110131-2) 2.2 cm 2 min 45 sec 0.80 cm/min 6 (F110131-3) 7.6 cm 1 hr50 min 0.07 cm/min 7 (F110131-4) 0.8 cm  1 min 0.80 cm/min 8 (F110131-5)4.2 cm 14 min 0.30 cm/min 9 (F110131-6) 1.4 cm 1 min 23 sc  1.01 cm/min10 (F110201-1)   14 cm 35 min 0.40 cm/min 11 (F110201-2)  0.4 cm 14 sec1.71 cm/min 12 (F110201-3)  12.6 cm  28 min 0.45 cm/min 13 (F110203-1) 3.2 cm 1 min 13 sec 2.63 cm/min 14 (F110203-2)  2.8 cm 5 min 37 sec 0.50cm/min 15 (F110203-3)  4.8 cm 013 min 50 sec  0.35 cm/min

It is understood that the examples and embodiments described herein arefor illustrative purposes only. Various modifications or changes inlight thereof will be suggested to persons skilled in the art and are tobe included within the spirit and purview of this application and thescope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

What is claimed is:
 1. A foamable formulation, said formulationcomprising: (i) dimethyl sulfoxide (DMSO); wherein DMSO is present in anamount ranging from about 12-80% w/w; (ii) a pharmaceutically activeagent; wherein the active agent is selected from the group consisting ofan anti-inflammatory steroid, a non-stereoidal anti-inflammatory drug,and a local anesthetic; and (iii) a polyalkylene glycol alkyl ether;wherein the formulation is foamable by manual aeration; and wherein theformulation comprises from 0 to 1% or from 30 to 45% w/w propellant. 2.The foamable formulation of claim 1, said formulation further comprisinga monohydric lower alcohol.
 3. The foamable formulation of claim 1,wherein said formulation comprises from 0 to 1% propellant.
 4. Thefoamable formulation of claim 1, wherein said formulation comprises15-80% w/w DMSO.
 5. The foamable formulation of claim 1, wherein saidactive agent is a non-steroidal anti-inflammatory drug.
 6. The foamableformulation of claim 5, wherein said non-steroidal anti-inflammatorydrug is ibuprofen or a diclofenac salt.
 7. The foamable formulation ofclaim 6, wherein said non-steroidal anti-inflammatory drug is ibuprofen;wherein the ibuprofen is present at 3-8% w/w; DMSO is present at 14-30%w/w; and the polyalkylene glycol alkyl ether is present at up to 3% w/w;wherein the formulation further comprises (iv) a diol and (v) water;wherein the formulation optionally further comprises a monohydric loweralcohol; wherein the diol is present at 5-9% w/w; the monohydric loweralcohol is present at 0-17% w/w; and the water is present at aconcentration of q.s.
 8. The foamable formulation of claim 6, whereinsaid diclofenac salt is diclofenac sodium.
 9. The foamable formulationof claim 8, wherein diclofenac sodium is present at 1-10% w/w, DMSO ispresent at 20-60% w/w, and the polyalkylene glycol alkyl ether ispresent at up to 10% w/w; wherein the formulation further comprises (iv)a monohydric alcohol, (v) propylene glycol, and (vi) water; and whereinthe monohydric alcohol is present at 1-50% w/w, propylene glycol ispresent at 1-15% w/w, and the water is present at a concentration ofq.s.
 10. The foamable formulation of claim 6, wherein the polyalkyleneglycol alkyl ether is present at up to 5% w/w.
 11. The foamableformulation of claim 10, further comprising 1-15% w/w glycerol.
 12. Thefoamable formulation of claim 10, wherein said polyalkylene glycol alkylether is a polyethylene glycol alkyl ether.
 13. The foamable formulationof claim 10, wherein said formulation further comprises a steroid. 14.The foamable formulation of claim 13, wherein said steroid ischolesterol; and wherein said formulation comprises at most 0.5% w/w ofsaid steroid.
 15. The foamable formulation of claim 13, wherein saidformulation further comprises a surfactant.
 16. The foamable formulationof claim 15, wherein said surfactant is a salt of an aryl sulfonate,alkyl sulfonate, aryl sulfate, or alkyl sulfate.
 17. The foamableformulation of claim 16, wherein said salt is sodium dodecyl benzenesulfonate, sodium laureth sulfate, or sodium lauryl sulfate.
 18. Thefoamable formulation of claim 13, wherein the formulation furthercomprises sodium carbonate.
 19. A foam comprising the foamableformulation of claim
 1. 20. The foam of claim 19, further comprisingair.
 21. The foam of claim 19, wherein the foam is a quick-breakingfoam.
 22. A method for treating a subject suffering from pain, saidmethod comprising the topical administration to an afflicted area ofsaid subject a therapeutically effective amount of the foamableformulation of claim 1, thereby treating the subject's pain.
 23. Themethod of claim 22, wherein said pain is associated with osteoarthritis.24. The method of claim 23, wherein said topical administration providesa reduction of pain over 12 weeks.
 25. The method of claim 23, whereinsaid formulation is applied one, two, three, or four times daily. 26.The foamable formulation of claim 1, wherein said formulation comprises12-48% w/w DMSO.
 27. The foamable formulation of claim 26, wherein saidformulation comprises 14-30% w/w DMSO.
 28. The foamable formulation ofclaim 1, wherein said polyalkylene glycol alkyl ether is present at upto 2% w/w.
 29. The foamable formulation of claim 4, wherein saidformulation comprises 25-80% w/w DMSO.
 30. A method for manually foamingthe foamable formulation of claim 1, the method comprising the steps of:(i) providing a dispenser comprising a reservoir operably linked influid communication with a release assembly; (ii) filling the reservoirwith the foamable formulation; and (iii) actuating the release assemblyto manually aerate the foamable formulation, thereby releasing a foamfrom the release assembly.